I can't get the full text of this article now [Jung et al., 2009: (http://www.springerlink.com/content/73r65221u5g14456/)], but the authors found that markers of depression and excessive stress (results on the usual tests or questionnaires, etc.) were higher in people whose serum calcium/magnesium (Ca/Mg) ratios were in the highest of three ranges of values. (The authors grouped the various serum Ca and Mg values into three ranges, or tertiles, and a higher score on one or more of the tests was taken as being an indication that the people had been experiencing more depression or anxiety, at the time they'd taken the tests.) Low serum Mg levels were also associated with more depression or anxiety.
That article looks interesting and is likely to have some validity to it, and one could interpret the results in a number of different contexts. I think elevations in serum Ca could produce depression by producing ATP depletion in neurons and astrocytes in parts of the brain or in cerebral vascular endothelial cells, and that ATP depletion could result from an excessive degree of activation of the coagulation cascade or from an excessive rate of calcium influx into neurons. An important effect of Mg (Mg2+) is to act as a mild Ca channel antagonist, either by acting extracellularly or intracellularly (). One thing that researchers hardly ever discuss in the literature is that the rate of Ca influx into cells does, in fact, tend to increase in response to increases in extracellular Ca [one example: Hennings et al., 1989: (http://www.ncbi.nlm.nih.gov/pubmed/2702726)]. That's just really important, and I can't emphasize enough the importance of that phenomenon. The way the authors of most articles describe the regulation of Ca influx, one would think Ca influx is so "strictly regulated" as to be more "inviolable" than "Fort Knox." The intracellular Ca concentrations are something like one 10,000th of the extracellular Ca concentration, normally, and the intracellular and intramitochondrial Ca concentrations are highly regulated. But they can, nonetheless, be increased or decreased to a meaningful extent, in my opinion, in response to increases or decreases in extracellular Ca. And Mg tends to block Ca channels to some extent, but it doesn't just behave like a pharmacological Ca channel antagonist. But the point is that an excessive rate of Ca influx into platelets can augment their thrombogenic effects, and excessive Ca influx into neurons, in the long term, tends to decrease dopaminergic transmission and worsen cognitive functioning and oppose all of the effects that occur in response to either an acute increase in Ca influx or that occur under conditions of tonic or phasic dopamine release, etc. Chronic stress can lead to excessive glutamatergic stimulation of noradrenergic neurons, in the locus ceruleus and other adrenergic cell groups, and dopaminergic neurons, such as in the ventral striatum, and thereby cause excessive Ca influx, and this tends to impair mitochondrial functioning and thereby cause ATP depletion [I shouldn't have to cite anything for this, given that it's so well-known, but here are some hastily-chosen articles that discuss that: Knochel, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10806294); Moghtader et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9434995)]. This can tend to decrease noradrenergic and dopaminergic transmission, and the mild NMDA-receptor antagonism of Mg or other weak NMDA-receptor antagonists can acutely and paradoxically sensitize dopaminergic neurons, for example, to D1 dopamine receptor activation [see here (http://hardcorephysiologyfun.blogspot.com/2009/03/adenosine-and-guanosine-in-animal.html) and, for example, Peeters et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12213297); Deep et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10529725); Arai et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12711097); Konradi et al., 1996: (http://www.jneurosci.org/cgi/reprint/16/13/4231)(http://www.ncbi.nlm.nih.gov/pubmed/8753884?dopt=Abstract); Tokuyama et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11408088); Boyce-Rustay et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16482087)].
The main point is that an excessive rate of Ca influx, in response to or in the presence of any of the countless stimuli that normally increase or regulate Ca influx, is just generally detrimental to all sorts of physiological processes and to energy metabolism in particular. Excessive Ca influx, in response to ischemia or other metabolic insults, activates Ca-dependent proteases that cause many more problems and worsen ATP depletion, ATP depletion impairs the capacity of cells and their mitochondria to buffer intracellular and intramitochondrial Ca concentrations, and so on (http://scholar.google.com/scholar?hl=en&q=calcium+dependent+protease+ischemia). Calcium influx is obviously essential, but the key point that is not obvious in the literature is that, in many or most cases, in my opinion, there is no shortage of Ca influx. And Ca influx and serum Ca are not in danger of being too low in most disease states. One would obviously want to discuss these things with one's doctor, however, and I'm just talking about these types of adjunctive approaches. Obviously, zinc and copper supplementation would be things to consider cutting out entirely, supposing one were interested in "addressing" a psychiatric condition, given the countless reports of neurotoxicity from excessive zinc supplementation and the known, endless problems associated with an excess of intracellular or extracellular copper and with copper supplementation in general. But these are just my opinions, and one's doctor is going to be the person to advise any given individual.
Showing posts with label Calcium. Show all posts
Showing posts with label Calcium. Show all posts
Sunday, September 20, 2009
Saturday, September 19, 2009
Heterogeneous Precipitation/Nucleation as a Mechanism Leading to "Chaos" in Magnesium and Phosphate Homeostasis
In their in vitro experiments at physiological pH values, Sheikh et al. (1989) [Shiekh et al., 1989: (http://www.pubmedcentral.nih.gov/picrender.fcgi?pmid=2910921&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2910921)] found that calcium (Ca2+) acetate was more effective in binding phosphate (Pi) than calcium carbonate was, and the authors also found that magnesium (Mg2+) was less effective than calcium in binding phosphate in vitro. However, Spiegel et al. (2007) [Spiegel et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17971314)] cited research (reference 10, cited on p. 421) in which the authors had made the argument that Mg2+ is likely to bind more phosphate than Ca2+ in vivo, primarily because less Mg2+ is going to be absorbed than Ca2+. I think that argument is likely to be valid, and the main thing would be to try to separate the administration of supplemental Mg2+ from the administration of Pi by at least 2 hours [Heaney, 2004: (http://www.mayoclinicproceedings.com/content/79/1/91.full.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/14708952)]. But the significance of the in vitro comparison of Ca acetate and Ca carbonate is that those experiments (Shiekh et al., 1989) provide an indirect explanation of one mechanism by which so-called Pi binders, including Ca alpha-ketoglutarate, reduce serum Pi in vivo. The mechanism is the formation, in the intestinal lumen, of heterogeneous precipitates (a.k.a. epitaxial growth of precipitates, heterotopic crystallization, etc.) that are amorphous or crystalline in their structures and that are composed of one or more anionic species, including urate or oxalate or ketoglutarate or other dicarboxylic acids (or even unconjugated bilirubin or bile salts, etc.) and Ca or Mg or both [(http://scholar.google.com/scholar?hl=en&q=epitaxial+phosphate+calcium)]. I should mention that the sequestration of Pi in the intestinal tract can't explain the reductions in serum Pi that the parenteral administration of amino acids has sometimes produced (http://hardcorephysiologyfun.blogspot.com/2009/09/reductions-in-serum-phosphate-induced.html). The reason is that the amino acids were administered parenterally and not enterally (i.e. jejunally or duodenally or orally or whatever variation on that). In any case, these are some of the articles showing the serum Pi-lowering effect of Ca alpha-ketoglutarate [Birck et al., 1999: (http://ndt.oxfordjournals.org/cgi/reprint/14/6/1475.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10383011); (http://scholar.google.com/scholar?hl=en&q=calcium+ketoglutarate+phosphate+binder)], and I don't think much of those calcium salts of organic anions as Pi binders or of Ca supplements in general. But it's interesting that bilirubin can form heterogeneous precipitates with Ca Pi, and "Ca Pi" supplementation decreased plasma bilirubin without altering the rates of urinary calcium or phosphate excretion [Van der Veere et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9024299)]. These are some other articles that show that effect (http://scholar.google.com/scholar?hl=en&q=calcium+phosphate+bilirubin).
Those mechanisms could mean that reasonable but not excessive intakes of Pi could serve to increase or "maintain" the excretion of bilirubin, but higher dosages could produce more of a nucleating effect and produce cholelithiasis (gallstones composed of mixed Ca and Mg precipitates of urate and phosphate, etc.). In the context of purine nucleotide supplementation, small changes in the ratios of phosphate, derived from nucleotide monophosphates or triphosphates, to exogenous-nucleotide-derived urate and xanthine could influence the formation of those types of precipitates. Adenosine that reaches the liver could increase Pi uptake by sequestering Pi in purine nucleotides and by increasing the activities of phosphofructokinase and other glycolytic enzymes, but an increase in biliary urate excretion (a significant amount can be excreted in the bile, rather than the urine), as a result, could increase the formation of heterogeneous precipitates with Ca Pi in the common bile duct and cause a biliary obstruction, etc. Those types of interactions would probably not be significant at most dosages, in my opinion, but it's potentially useful to be aware of that type of thing. That type of "extreme" scenario would be unlikely in anyone who is using reasonable dosages but could be more likely to occur in a person who is diabetic or insulin-resistant, for example.
It's interesting that the absorption of Mg, in particular, can also be drastically decreased by its binding to and sequestration by bile acids and unabsorbed fatty acids in people who display malabsorption due to liver disease, etc., and I've cited research on that in past postings. The dosages of Mg that researchers had to use to overcome that binding effect and just correct the deficiency state, in children who were undergoing treatment for liver disease, works out to a dose of 2380 mg/day of Mg for a 70-kg human [Heubi et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9285381); (http://hardcorephysiologyfun.blogspot.com/2009/01/articles-on-pantothenic-acid-vitamin-b5.html)]. That means that most of that 2,380 mg (or equivalent dosages in children) was not even available for absorption. And those children weren't even having to consider the binding of Mg by phosphate, etc. There's actually a scaling factor of about 2 that's sometimes used to convert children's dosages to adults' dosages, but I think that scaling factor is only applicable to children within a fairly narrow range of ages. But even supposing it's 1,190 mg of Mg that's being bound by endogenous bile salts and dietary fatty acids in an adult who has liver disease, it's relevant that as many as 20-30 percent of Americans display some degree of nonalcoholic fatty liver disease. A gram of phosphate can bind up to 1800 mg of Mg. That means the intake of a person who is not taking supplemental Mg and who is adding a gram of phosphate to his or her diet, through meat intake or some other route, could conceivably be receiving a daily Mg intake of "negative 2690 mg," assuming the person gets the usual, measly 300 mg/day from foods. In reality, the Pi wouldn't bind that much Mg in vivo, especially if the Mg were taken at a different time. But the point is that the magnitude of the Mg binding can be very large, and the nucleating effect of some of these endogenous, anionic compounds could create complex dose-response relationships for something like Pi. The formation of heterogeneous precipitates of bilirubin and calcium phosphate could also explain the apparent "phosphate-sparing" effect of calcium phosphate, even though calcium phosphate is more or less insoluble (see Heaney, 2004). (The calcium phosphate could remain insoluble and promote the nucleation of complexes of calcium and bilirubin, thereby reducing the amount of calcium that would be available to bind to dietary phosphate. That could increase the amount of phosphate that would be available for absorption. I don't quite understand the stoichiometries of the binding of soluble calcium with bilirubin and calcium phosphate or magnesium phosphate to form insoluble, heterogeneous precipitates, but it's likely that no one understands those issues.)
Those mechanisms could mean that reasonable but not excessive intakes of Pi could serve to increase or "maintain" the excretion of bilirubin, but higher dosages could produce more of a nucleating effect and produce cholelithiasis (gallstones composed of mixed Ca and Mg precipitates of urate and phosphate, etc.). In the context of purine nucleotide supplementation, small changes in the ratios of phosphate, derived from nucleotide monophosphates or triphosphates, to exogenous-nucleotide-derived urate and xanthine could influence the formation of those types of precipitates. Adenosine that reaches the liver could increase Pi uptake by sequestering Pi in purine nucleotides and by increasing the activities of phosphofructokinase and other glycolytic enzymes, but an increase in biliary urate excretion (a significant amount can be excreted in the bile, rather than the urine), as a result, could increase the formation of heterogeneous precipitates with Ca Pi in the common bile duct and cause a biliary obstruction, etc. Those types of interactions would probably not be significant at most dosages, in my opinion, but it's potentially useful to be aware of that type of thing. That type of "extreme" scenario would be unlikely in anyone who is using reasonable dosages but could be more likely to occur in a person who is diabetic or insulin-resistant, for example.
It's interesting that the absorption of Mg, in particular, can also be drastically decreased by its binding to and sequestration by bile acids and unabsorbed fatty acids in people who display malabsorption due to liver disease, etc., and I've cited research on that in past postings. The dosages of Mg that researchers had to use to overcome that binding effect and just correct the deficiency state, in children who were undergoing treatment for liver disease, works out to a dose of 2380 mg/day of Mg for a 70-kg human [Heubi et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9285381); (http://hardcorephysiologyfun.blogspot.com/2009/01/articles-on-pantothenic-acid-vitamin-b5.html)]. That means that most of that 2,380 mg (or equivalent dosages in children) was not even available for absorption. And those children weren't even having to consider the binding of Mg by phosphate, etc. There's actually a scaling factor of about 2 that's sometimes used to convert children's dosages to adults' dosages, but I think that scaling factor is only applicable to children within a fairly narrow range of ages. But even supposing it's 1,190 mg of Mg that's being bound by endogenous bile salts and dietary fatty acids in an adult who has liver disease, it's relevant that as many as 20-30 percent of Americans display some degree of nonalcoholic fatty liver disease. A gram of phosphate can bind up to 1800 mg of Mg. That means the intake of a person who is not taking supplemental Mg and who is adding a gram of phosphate to his or her diet, through meat intake or some other route, could conceivably be receiving a daily Mg intake of "negative 2690 mg," assuming the person gets the usual, measly 300 mg/day from foods. In reality, the Pi wouldn't bind that much Mg in vivo, especially if the Mg were taken at a different time. But the point is that the magnitude of the Mg binding can be very large, and the nucleating effect of some of these endogenous, anionic compounds could create complex dose-response relationships for something like Pi. The formation of heterogeneous precipitates of bilirubin and calcium phosphate could also explain the apparent "phosphate-sparing" effect of calcium phosphate, even though calcium phosphate is more or less insoluble (see Heaney, 2004). (The calcium phosphate could remain insoluble and promote the nucleation of complexes of calcium and bilirubin, thereby reducing the amount of calcium that would be available to bind to dietary phosphate. That could increase the amount of phosphate that would be available for absorption. I don't quite understand the stoichiometries of the binding of soluble calcium with bilirubin and calcium phosphate or magnesium phosphate to form insoluble, heterogeneous precipitates, but it's likely that no one understands those issues.)
Wednesday, September 16, 2009
Crucially-Important and Mind-Bending Interactions in Phosphate and Magnesium Homeostasis
The authors of these articles [Thumfart et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18701629); Wei et al., 2006: (http://www.pdiconnect.com/cgi/reprint/26/3/366.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/16722031)] have discussed the evidence that serum magnesium (Mg) levels tend to be inversely correlated with serum parathyroid hormone (PTH) levels, and Wei et al. (2006) discussed all of the evidence that magnesium repletion can be protective against calcification and thrombosis and markers of cardiovascular disease. The inverse relationship between the serum Mg and PTH levels is not widely known in the literature, and I've only recently even seen research on it. It's really important, and Mg is just really important, in general, in my opinion. Most of the research and articles on Mg and PTH have focused on the hypocalcemic hypoparathyroidism that can occur in severe Mg deficiency, but repletion of Mg in severely-deficient animals or humans only increases serum calcium (Ca) back to normal levels, by increasing (restoring) the normal capacity of the parathyroid glands to release PTH in response to decreases in serum Ca. At serum Mg levels or dietary Mg supplies that are higher than those that are required for those most basic functions, Mg is thought to suppress PTH levels by acting as a "weak" activator, like a partial agonist, almost, of the calcium-sensing receptor(s) that mediate the suppression of PTH release in response to increases in serum Ca (Thumfart et al., 2008). Paradoxically, Mg can also increase urinary calcium excretion by reducing the reabsorption of calcium in the renal tubules (Thumfart et al., 2008). It's important to note that that increase in urinary Ca excretion would be likely to occur in conjunction with the decreases in the risk of nephrocalcinosis that researchers have generally found in response to increases in Mg intake. In the case of phosphate (Pi) repletion, the decreases in urinary Ca excretion are thought to result from the suppression of PTH-mediated bone resorption. Thus, Pi is thought to actually reduce the amount of Ca that is filtered in the glomeruli, and Mg may partially act by inhibiting Ca reabsorption in the renal tubules (proximal tubules and distal tubules). But the research I cited above suggests that Mg can increase the rate of urinary Ca excretion and even decrease the serum Ca levels and exert a concomitant, suppressive effect on PTH release. That's a really unusual set of effects. Pi can decrease serum Ca (an effect that is probably undesirable) and decrease urinary calcium excretion but can also elevate PTH levels, and that's an effect that could be attenuated, for better or worse, by an increase in Mg availability to the parathyroid glands or the Ca sensing proteins in the renal tubules, etc. Additionally, many of the bizarre derangements in the homeostatic regulation of Ca and Pi that have been found in response to long-term, excessive Pi supplementation could result, in some cases, from Mg depletion. I also get the general sense that a "high" Pi intake will tend to produce plasma volume expansion and lead to a reduction in urinary sodium excretion, and that could tend to oppose the natriuretic effect that high doses of Mg can sometimes produce. Another way of looking at it would be to say that a high or excessive Pi intake may produce plasma volume expansion by reducing Mg absorption or by increasing Mg turnover by other mechanisms, and Mg has sometimes produced low-level diuretic effects [Walker et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9861593?dopt=Abstract)], by mechanisms that aren't clear.
Incidentally, this is another article that includes a discussion of the antithrombotic effects that increases in Mg availability can produce [Maier et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15158909)], and I've been meaning to collect some of the articles that show the antithrombotic effects of Mg repletion or of elevations in the extracellular Mg levels (the steady-state, extracellular Mg levels are not necessarily or even usually going to be elevated much or at all, even in response to Mg supplementation that increases intracellular Mg levels).
What's really interesting is that low serum Mg and low serum Pi tend to go hand in hand and produce many of the same manifestations, including rhabdomyolysis and decreases in red blood cell (RBC) deformability and hemolytic anemia and decreases in RBC 2,3-DPG and ATP, etc. Oken et al. (1971) [Oken et al., 1971: (http://www.bloodjournal.org/cgi/reprint/38/4/468.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/5571433)] found that Mg deficiency caused hemolytic anemia, reticulocytosis in combination with erythroid hyperplasia in the bone marrow (basically meaning that some erythroid colony-forming units in the bone marrow may be enlarged and hyperresponsive to erythropoietin and that the immature RBC's are more numerous and are also undergoing apoptosis at a high rate, because of Mg depletion), decreases in serum phosphorus (and, hence, serum Pi, also), and decreases in the RBC 2,3-DPG and ATP concentrations and in the overall glycolytic activity in RBC's. Piomelli et al. (1973) [Piomelli et al., 1973: (http://www.bloodjournal.org/cgi/reprint/41/3/451.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4690142)] also found hemolytic anemia in Mg depleted rats and cited research that had shown hypophosphatemia and hypomagnesemia to occur concomitantly in animals and humans.
It's also really important to note that a lot of articles have shown that Mg supplementation at dosages that would produce "desirable" effects, in my opinion, can decrease serum Pi or produce outright hypophosphatemia. And Pi supplementation can produce hypomagnesemia and intracellular Mg depletion. I think that the amounts of supplemental Mg that might be required to compensate for those effects of Pi repletion could be large and could be too high for many people to easily "accept." But, if the Mg is binding to Pi in the GI tract and precipitating, it's not going to be absorbed (there could be some solubilization in response to pH changes along the GI tract, but, for the most part, the precipitation is going to be permanent and is going to mean that the Mg and Pi are "lost"). One way of considering this would be to say that some percentage of a dose of Pi, from the diet or low-dose supplement, under a doctor's supervision, is going to be absorbed and some percentage is going to not be absorbed and probably bind some amounts of Mg and Ca. The intestinal absorption of Ca and the maintenance of serum Ca and renal Ca reabsorption are much more effectively maintained and regulated, in my opinion. Researchers have noted that the serum Ca is relatively stable, even in terms of circadian changes, than the serum Pi. The serum Pi fluctuates wildly throughout the day and in response to exercise, etc. I think the serum Mg levels are not as unstable as the serum Pi levels are, but the intracellular Mg concentrations are very easily depleted, such as in response to catecholaminergic stimulation, etc. Assuming one is using any supplemental Mg and Pi under a doctor's supervision, there's really a need to not be afraid to increase the supplemental intake of Mg, from Mg salts (such as magnesium hydroxide or magnesium oxide) slowly but relatively freely, to compensate for the reductions in absorption that are likely to result from the extra Pi. It wouldn't be a good idea to increase the Pi as freely as one might increase one's Mg intake, but part of the point of this is that an adequate degree of Mg availability is really obligatory for many of the effects of Pi repletion to be sustained in the longer term. One way to approach this type of problem would be to decide on some dosage of supplemental Mg that is tolerable and safe, under a doctor's supervision, and then to increase the ratio of Pi to Ca, assuming one would want to do this, in the first place. That would allow one to evaluate the effect of the Pi increase, from food or low-dose supplements, with the "knowledge" of the baseline effects that the initial Mg dosage produced. There's still a tendency for a lot of the research to focus on the most severe manifestations of the depletion of Mg or Pi or both (hypophosphatemia or hypomagnesemia), but intracellular Pi and Mg depletion tend to occur long before overt hypomagnesemia and hypophosphatemia occur. In any case, those articles I cited are just the tip of the iceberg. Resistance exercise that is done correctly, for example, can drastically deplete intracellular Mg and Pi concentrations, but the tendency has been to focus, in the case of Pi and RBC 2,3-DPG, on the short-term, post-exercise increases in RBC 2,3-DPG or serum Pi. But the more important issues have to do with the changes that occur in the days after the workout. It doesn't make sense to say that resistance exercise that correctly emphasizes the eccentric movement is going to increase RBC 2,3-DPG in the hours after exercise and then cause those levels and the intracellular Pi levels in skeletal or cardiac myocytes to also remain persistently elevated. Where would the Pi come from. It's likely that intense exercise can produce drastic depletions in intracellular Pi levels, but I haven't seen a lot of data on that. The increases in catecholaminergic transmission during resistance exercise would be expected to produce a significant depletion of intracellular Mg, and this has been shown to occur. And beta-adrenoreceptor agonists can produce hypophosphatemia and hypomagnesemia in the long term, etc. Even lowly L-methylfolate could reasonably be expected to increase Pi and Mg turnover, in my opinion, as a result of its apparent catecholaminergic effects.
Incidentally, this is another article that includes a discussion of the antithrombotic effects that increases in Mg availability can produce [Maier et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15158909)], and I've been meaning to collect some of the articles that show the antithrombotic effects of Mg repletion or of elevations in the extracellular Mg levels (the steady-state, extracellular Mg levels are not necessarily or even usually going to be elevated much or at all, even in response to Mg supplementation that increases intracellular Mg levels).
What's really interesting is that low serum Mg and low serum Pi tend to go hand in hand and produce many of the same manifestations, including rhabdomyolysis and decreases in red blood cell (RBC) deformability and hemolytic anemia and decreases in RBC 2,3-DPG and ATP, etc. Oken et al. (1971) [Oken et al., 1971: (http://www.bloodjournal.org/cgi/reprint/38/4/468.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/5571433)] found that Mg deficiency caused hemolytic anemia, reticulocytosis in combination with erythroid hyperplasia in the bone marrow (basically meaning that some erythroid colony-forming units in the bone marrow may be enlarged and hyperresponsive to erythropoietin and that the immature RBC's are more numerous and are also undergoing apoptosis at a high rate, because of Mg depletion), decreases in serum phosphorus (and, hence, serum Pi, also), and decreases in the RBC 2,3-DPG and ATP concentrations and in the overall glycolytic activity in RBC's. Piomelli et al. (1973) [Piomelli et al., 1973: (http://www.bloodjournal.org/cgi/reprint/41/3/451.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4690142)] also found hemolytic anemia in Mg depleted rats and cited research that had shown hypophosphatemia and hypomagnesemia to occur concomitantly in animals and humans.
It's also really important to note that a lot of articles have shown that Mg supplementation at dosages that would produce "desirable" effects, in my opinion, can decrease serum Pi or produce outright hypophosphatemia. And Pi supplementation can produce hypomagnesemia and intracellular Mg depletion. I think that the amounts of supplemental Mg that might be required to compensate for those effects of Pi repletion could be large and could be too high for many people to easily "accept." But, if the Mg is binding to Pi in the GI tract and precipitating, it's not going to be absorbed (there could be some solubilization in response to pH changes along the GI tract, but, for the most part, the precipitation is going to be permanent and is going to mean that the Mg and Pi are "lost"). One way of considering this would be to say that some percentage of a dose of Pi, from the diet or low-dose supplement, under a doctor's supervision, is going to be absorbed and some percentage is going to not be absorbed and probably bind some amounts of Mg and Ca. The intestinal absorption of Ca and the maintenance of serum Ca and renal Ca reabsorption are much more effectively maintained and regulated, in my opinion. Researchers have noted that the serum Ca is relatively stable, even in terms of circadian changes, than the serum Pi. The serum Pi fluctuates wildly throughout the day and in response to exercise, etc. I think the serum Mg levels are not as unstable as the serum Pi levels are, but the intracellular Mg concentrations are very easily depleted, such as in response to catecholaminergic stimulation, etc. Assuming one is using any supplemental Mg and Pi under a doctor's supervision, there's really a need to not be afraid to increase the supplemental intake of Mg, from Mg salts (such as magnesium hydroxide or magnesium oxide) slowly but relatively freely, to compensate for the reductions in absorption that are likely to result from the extra Pi. It wouldn't be a good idea to increase the Pi as freely as one might increase one's Mg intake, but part of the point of this is that an adequate degree of Mg availability is really obligatory for many of the effects of Pi repletion to be sustained in the longer term. One way to approach this type of problem would be to decide on some dosage of supplemental Mg that is tolerable and safe, under a doctor's supervision, and then to increase the ratio of Pi to Ca, assuming one would want to do this, in the first place. That would allow one to evaluate the effect of the Pi increase, from food or low-dose supplements, with the "knowledge" of the baseline effects that the initial Mg dosage produced. There's still a tendency for a lot of the research to focus on the most severe manifestations of the depletion of Mg or Pi or both (hypophosphatemia or hypomagnesemia), but intracellular Pi and Mg depletion tend to occur long before overt hypomagnesemia and hypophosphatemia occur. In any case, those articles I cited are just the tip of the iceberg. Resistance exercise that is done correctly, for example, can drastically deplete intracellular Mg and Pi concentrations, but the tendency has been to focus, in the case of Pi and RBC 2,3-DPG, on the short-term, post-exercise increases in RBC 2,3-DPG or serum Pi. But the more important issues have to do with the changes that occur in the days after the workout. It doesn't make sense to say that resistance exercise that correctly emphasizes the eccentric movement is going to increase RBC 2,3-DPG in the hours after exercise and then cause those levels and the intracellular Pi levels in skeletal or cardiac myocytes to also remain persistently elevated. Where would the Pi come from. It's likely that intense exercise can produce drastic depletions in intracellular Pi levels, but I haven't seen a lot of data on that. The increases in catecholaminergic transmission during resistance exercise would be expected to produce a significant depletion of intracellular Mg, and this has been shown to occur. And beta-adrenoreceptor agonists can produce hypophosphatemia and hypomagnesemia in the long term, etc. Even lowly L-methylfolate could reasonably be expected to increase Pi and Mg turnover, in my opinion, as a result of its apparent catecholaminergic effects.
Monday, September 7, 2009
Interactions of Phosphate and Calcium Homeostasis with the Coagulation Cascade: Potential Relevance to Depression and Other Psychiatric Symptoms
So the "bottom-line," "take-home" message of that last posting is that, in susceptible individuals or individuals in whom the coagulation cascade has been transiently or mildly activated by infectious mono or influenza, an increase in serum calcium within the normal range could produce depression or psychiatric symptoms by producing low-level thrombogenic effects (effects that essentially disturb mitochondrial functioning, as the feed-forward activation of the coagulation cascade essentially always does), and reducing serum calcium by reducing the dietary calcium or vitamin D intake could ameliorate those effects. Increasing the ratio of the phosphate to calcium intake could be a superior way of addressing those potentially-thrombogenic effects (and calcium influx promoting effects, in neurons) of increases in serum calcium. And idiosyncratic effects of glutamine supplementation might be addressed by decreasing the vitamin D or calcium intake or increasing the relative intake of phosphate, to some small extent, given the potential for slight "calcemic" and hypophosphatemic effects of glutamine. It's possible that an increase in serum phosphate would reduce calcium influx into platelets, given that increases in phosphate availability have reduced stimulus-induced intracellular calcium influx in beta-cells, for example, if memory serves (see past postings), and in other cell types. That's thought to be one mechanism underlying magnesium's antithrombotic effects (and relative absence of hemorrhagic effects).
I don't have time to go into the research, but, in my opinion, some of the research that would seem to rule out a role for the activation of the coagulation cascade in depression (http://scholar.google.com/scholar?q=coagulation+psychiatry&hl=en) does not rule it out, given that research in people with lupus and research on the coagulation cascade in general have shown that localized endothelial cell activation, such as in cerebral blood vessels, can occur and can cause localized microthrombi or low-level thromboses without producing measurable changes in the systemic coagulation parameters. Blood tests of coagulation parameters are notoriously insensitive and problematic, in my opinion. This is not a scientific statement, but, if it were possible to easily evaluate coagulation function, then monitoring people on warfarin wouldn't be so difficult and complex for both doctors and patients (the people taking warfarin, etc.), in my opinion. The coagulation cascade is extremely complex, and quantitative data on coagulation parameters are not going to tell one all that much about the individual and tissue-restricted effects of that state in any one person. The INR, for example, is very insensitive and displays a semi-logarithmic relationship with changes in the serum prothrombin levels, etc. I tend to think the ex vivo tests on platelet function are also not always going to have relevance to tissue-restricted (or endothelial-site-restricted) thrombogenic effects in the brain, for example. Benign intracranial hypertension/idiopathic intracranial hypertension commonly produces psychiatric symptoms, but that type of disease state may just be a slightly more extreme state along a spectrum of low-level thrombogenic changes that could potentially contribute to some forms of severe depression or chronic fatigue syndrome, etc. Those articles about visual dimming in depression could also indicate that low-level activation of the coagulation cascade is occurring, given the common occurrence of visual dimming in idiopathic intracranial hypertension (and the fact that idiopathic intracranial hypertension is thought to be not-infrequently caused, in part, by venous sinus thrombosis). Magnesium can also produce antithrombotic effects and may, in my opinion, be a lot less likely to cause bleeding, upon adjustment to a dose increase in 1-2 days, than many or most of the many other compounds that influence platelet activation and the coagulation cascade. In any case, it's worthwhile to remember that the use of Ginkgo biloba extracts has been associated with intracranial hemorrhages in many case reports (http://hardcorephysiologyfun.blogspot.com/2008/12/ginkgo-biloba-extracts-and-intracranial.html), and many compounds can reduce coagulation by mechanisms that could be very dangerous and unpredictable. So one would want to talk to one's doctor about this type of thing. Purines have produced antithrombotic effects in a lot of animal studies and appear to be a lot less likely to cause bleeding than most of these other physiological approaches, but that's just my opinion, based on my experiences during infectious mono, several years ago. These are all, obviously, just my opinions.
I don't have time to go into the research, but, in my opinion, some of the research that would seem to rule out a role for the activation of the coagulation cascade in depression (http://scholar.google.com/scholar?q=coagulation+psychiatry&hl=en) does not rule it out, given that research in people with lupus and research on the coagulation cascade in general have shown that localized endothelial cell activation, such as in cerebral blood vessels, can occur and can cause localized microthrombi or low-level thromboses without producing measurable changes in the systemic coagulation parameters. Blood tests of coagulation parameters are notoriously insensitive and problematic, in my opinion. This is not a scientific statement, but, if it were possible to easily evaluate coagulation function, then monitoring people on warfarin wouldn't be so difficult and complex for both doctors and patients (the people taking warfarin, etc.), in my opinion. The coagulation cascade is extremely complex, and quantitative data on coagulation parameters are not going to tell one all that much about the individual and tissue-restricted effects of that state in any one person. The INR, for example, is very insensitive and displays a semi-logarithmic relationship with changes in the serum prothrombin levels, etc. I tend to think the ex vivo tests on platelet function are also not always going to have relevance to tissue-restricted (or endothelial-site-restricted) thrombogenic effects in the brain, for example. Benign intracranial hypertension/idiopathic intracranial hypertension commonly produces psychiatric symptoms, but that type of disease state may just be a slightly more extreme state along a spectrum of low-level thrombogenic changes that could potentially contribute to some forms of severe depression or chronic fatigue syndrome, etc. Those articles about visual dimming in depression could also indicate that low-level activation of the coagulation cascade is occurring, given the common occurrence of visual dimming in idiopathic intracranial hypertension (and the fact that idiopathic intracranial hypertension is thought to be not-infrequently caused, in part, by venous sinus thrombosis). Magnesium can also produce antithrombotic effects and may, in my opinion, be a lot less likely to cause bleeding, upon adjustment to a dose increase in 1-2 days, than many or most of the many other compounds that influence platelet activation and the coagulation cascade. In any case, it's worthwhile to remember that the use of Ginkgo biloba extracts has been associated with intracranial hemorrhages in many case reports (http://hardcorephysiologyfun.blogspot.com/2008/12/ginkgo-biloba-extracts-and-intracranial.html), and many compounds can reduce coagulation by mechanisms that could be very dangerous and unpredictable. So one would want to talk to one's doctor about this type of thing. Purines have produced antithrombotic effects in a lot of animal studies and appear to be a lot less likely to cause bleeding than most of these other physiological approaches, but that's just my opinion, based on my experiences during infectious mono, several years ago. These are all, obviously, just my opinions.
Reductions in Serum Phosphate Induced by Supplementation With Free-Form Amino Acids: Interactions of Phosphate Homeostasis with Renal Ammoniagenesis
These articles [Heidland et al., 1978: (http://www.ajcn.org/cgi/reprint/31/10/1784.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/707333); Lamiell et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2108005)] show that supplementation with free-form amino acids, particularly in conjunction with a low- or "no-phosphate" diet (Lamiell et al., 1990), can fairly drastically reduce serum phosphate and also increase serum calcium. I've discussed some of these articles in past postings (http://hardcorephysiologyfun.blogspot.com/2009/02/potential-for-hypophosphatemia-or.html). Heidland et al. (1978) found that the serum calcium levels varied inversely with the serum phosphorus levels, in the people who had been given supplemental essential amino acids, and the authors suggested that that inverse relationship might have resulted from the increases in serum 1alpha,25-dihydroxyvitamin D3 (calcitriol, hormonal vitamin D, HVD) and the resorptive effect of an increase in serum HVD (?). These are really good articles, and I've never seen anyone mention that increase in "calcium mobilization from bone" (Heidland et al., 1978, p. 1791) in response to an increase in serum HVD. It's not widely-recognized, but there is a lot of research showing that increases in serum HVD can produce effects that are basically opposite to those of increases in autocrine or paracrine HVD (HVD that is formed in response to increases in extracellular 25-hydroxyvitamin D and that acts on nearby cells or in the same cell in which it is formed), and those paradoxical effects seem to show up more in relation to the calcemic or calcium-transport-modifying effects of HVD. For example, increases in HVD are known to be somewhat permissive with respect to soft-tissue calcification in animals, but increases in 25-hydroxyvitamin D, in the absence of concomitant increases in serum calcium (effects that are potentially more likely to occur in response to UV-induced increases in vitamin D than in response to oral vitamin D, in my opinion, given that oral vitamin D is likely to be more calcemic, etc.), have generally not increased soft tissue calcification and may have the potential to decrease soft-tissue calcification by, in theory, helping to prevent the osteoblastic differentiation of smooth muscle cells, etc. But combining high-dose vitamin D3 with high-dose calcium supplements has the potential to cause problems, and Heidland et al. (1978) suggested that the association of the amino acid supplementation with hypercalcemia, in some people, had been a result of the extra calcium supplementation (coupled with the relative absence of dietary phosphate).
A lot of these articles on these strategies for managing hyperparathyroidism and hyperphosphatemia in people who have kidney failure only look at serum phosphate or serum parathyroid hormone (PTH) levels and don't consider the levels of intracellular phosphate or the context in which the increases in PTH levels are occurring, and these are problematic aspects of a lot of these articles (I'm not talking about the ones I cited above). Lamiell et al. (1990) found, for example, that, after the second administration of the zero-phosphate parenteral nutrition formula was given to a person (they gave it and discontinued it a few times before they determined that hypophosphatemia or intracellular phosphate depletion, in addition to hyperammonemia, was causing the encephalopathy, and this is understandable), the encephalopathy occurred when the serum phosphate was normal. Lamiell et al. (1990) attributed that encephalopathic episode to hyperammonemia, and that's plausible, but it's important to remember that the intracellular inorganic and organic (i.e. ATP and ADP, phosphocreatine, etc.) phosphate levels can be significantly depleted in a person whose steady-state serum inorganic phosphate levels are normal [for example, Ambuhl et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10561144)]. Many most articles whose authors have measured the intracellular 2,3-diphosphoglycerate (2,3-DPG) concentrations in red blood cells have shown that have shown that those concentrations don't correlate at all with serum phosphate levels. I also think there's a danger in thinking that these derangements in calcium and phosphate homeostasis will only occur in people who have renal failure, but supplemental phosphate decreased urinary calcium excretion in normal people who had evidently not been exhibiting hypercalciuria [Heaney and Recker, 1987: (http://www.ncbi.nlm.nih.gov/pubmed/2851341)]. So some of these unspoken assumptions, such as the assumption that massive doses of calcium are going to not cause hypercalcemia or pathological effects in people who do not have kidney disease, in short-term trials with calcium supplements have the potential to be invalid.
The mechanisms by which free-form amino acids can decrease serum phosphate are not well-understood, but Heidland et al. (1978) noted that the persistence of the decreases in serum phosphate over the long term, in some people who are given supplemental amino acids, argues against the idea that the hypophosphatemic effect is a result of the "refeeding syndrome" or even something akin to it. I think it's caused by changes in the interactions of renal ammoniagenesis with the mechanisms governing phosphate reabsorption in the proximal tubules, and those interactions basically boil down to changes in acid-base homeostasis. For example, the acute, supplemental-glutamine-induced increases in serum bicarbonate that can occur in humans could be expected to favor an increase in phosphate transport into cells. There probably is an increase in phosphate uptake into cells, in response to some amino acids, but it's noteworthy that excessive or high doses of some mixtures of free-form amino acids seem to be more likely to produce hyperammonemia than protein does. Lamiell et al. (1990) attributed that to the absence of arginine in some mixtures, and that's conceivable. But it might be a result of the kinetics of the absorption of free-form amino acids. Their absorption is going to be much more rapid than the absorption of protein-derived amino acids, and that could overwhelm the liver's capacity for ureagenesis. It's also possible that increases in phosphate utilization (or loss of phosphate in the urine, induced by the amino acids) decreases the availability of intracellular inorganic and organic phosphate in a way that impairs the activities of hepatic urea cycle enzymes. But one possibility that seems plausible to me is that amino acids increase urinary phosphate loss and that the loss of phosphate increases renal ammoniagenesis to a degree that is significant enough to disturb the systemic acid-base homeostatic mechanisms and actually contribute to hyperammonemia. Under some circumstances, the overall urea cycle activity is thought to be an important factor in influencing systemic acid-base homeostasis, and Haussinger et al. (1990) [cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/02/urea-cycle-renal-glutaminase-activity.html); Haussinger et al., 1990: ([Haussinger et al., 1990: (http://www.springerlink.com/content/l2vx314521367706/)] basically found that even mild liver dysfunction was associated with a failure of renal ammoniagenesis to downregulate in response to systemic metabolic alkalosis. So, in a normal person, glutamine supplementation might acutely increase serum bicarbonate or only increase it on some days, such as on a day of intense exercise (in response to acidosis), but massive doses of glutamine or other essential amino acids that increase renal glutamine availability (glutaminase and the glutamine cycle are important in the regulation of renal ammoniagenesis, in response to metabolic acidosis) could contribute to the persistently-alkalotic state that can occur even in compensated liver disease, as discussed by Haussinger et al. (1990).
It's worth noting that alkalosis doesn't just increase phosphate uptake into cells (it tends to decrease intracellular phosphate availability in the long-term or even short term, because the uptake into cells provides phosphate to some cells at the expense of others, given the usual, alkalosis-induced reduction in serum phosphate) but impairs the unloading of oxygen from hemoglobin in a "2,3-DPG-depletion-independent" manner. That's one reason why bicarbonate administration can be so disastrous in a person who is hypophosphatemic, as discussed in past postings. One would think that the alkalosis-induced uptake (it's thought to partially be a result of the alkalosis-induced activation of glycolytic enzymes) of phosphate would increase 2,3-DPG levels, but it tends to not be the case in hypophosphatemia. It might be that more 2,3-DPG is driven into skeletal muscle myocytes or other cells that are not red blood cells, or it might be that the 2,3-DPG-independent "impairment" in the unloading of oxygen from hemoglobin tends to offset any potential for an increase in 2,3-DPG formation to occur in response to the alkalosis-induced increase in phosphate uptake by red blood cells. In any case, an inappropriate and persistent increase in renal ammoniagenesis could cause an ammonia-mediated impairment of TCA cycle activity in proximal tubule cells, given that ammonia excesses are known to inhibit TCA cycle enzymes and other mitochondrial enzymes and to interfere with energy metabolism by all sorts of mechanisms. That metabolic toxicity could reduce phosphate reabsorption by proximal tubule cells and exacerbate phosphaturia. Some of these articles by Ambuhl and colleagues (http://scholar.google.com/scholar?hl=en&q=ambuhl+phosphate) look promising as sources of information on those types of mechanisms.
A lot of these articles on these strategies for managing hyperparathyroidism and hyperphosphatemia in people who have kidney failure only look at serum phosphate or serum parathyroid hormone (PTH) levels and don't consider the levels of intracellular phosphate or the context in which the increases in PTH levels are occurring, and these are problematic aspects of a lot of these articles (I'm not talking about the ones I cited above). Lamiell et al. (1990) found, for example, that, after the second administration of the zero-phosphate parenteral nutrition formula was given to a person (they gave it and discontinued it a few times before they determined that hypophosphatemia or intracellular phosphate depletion, in addition to hyperammonemia, was causing the encephalopathy, and this is understandable), the encephalopathy occurred when the serum phosphate was normal. Lamiell et al. (1990) attributed that encephalopathic episode to hyperammonemia, and that's plausible, but it's important to remember that the intracellular inorganic and organic (i.e. ATP and ADP, phosphocreatine, etc.) phosphate levels can be significantly depleted in a person whose steady-state serum inorganic phosphate levels are normal [for example, Ambuhl et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10561144)]. Many most articles whose authors have measured the intracellular 2,3-diphosphoglycerate (2,3-DPG) concentrations in red blood cells have shown that have shown that those concentrations don't correlate at all with serum phosphate levels. I also think there's a danger in thinking that these derangements in calcium and phosphate homeostasis will only occur in people who have renal failure, but supplemental phosphate decreased urinary calcium excretion in normal people who had evidently not been exhibiting hypercalciuria [Heaney and Recker, 1987: (http://www.ncbi.nlm.nih.gov/pubmed/2851341)]. So some of these unspoken assumptions, such as the assumption that massive doses of calcium are going to not cause hypercalcemia or pathological effects in people who do not have kidney disease, in short-term trials with calcium supplements have the potential to be invalid.
The mechanisms by which free-form amino acids can decrease serum phosphate are not well-understood, but Heidland et al. (1978) noted that the persistence of the decreases in serum phosphate over the long term, in some people who are given supplemental amino acids, argues against the idea that the hypophosphatemic effect is a result of the "refeeding syndrome" or even something akin to it. I think it's caused by changes in the interactions of renal ammoniagenesis with the mechanisms governing phosphate reabsorption in the proximal tubules, and those interactions basically boil down to changes in acid-base homeostasis. For example, the acute, supplemental-glutamine-induced increases in serum bicarbonate that can occur in humans could be expected to favor an increase in phosphate transport into cells. There probably is an increase in phosphate uptake into cells, in response to some amino acids, but it's noteworthy that excessive or high doses of some mixtures of free-form amino acids seem to be more likely to produce hyperammonemia than protein does. Lamiell et al. (1990) attributed that to the absence of arginine in some mixtures, and that's conceivable. But it might be a result of the kinetics of the absorption of free-form amino acids. Their absorption is going to be much more rapid than the absorption of protein-derived amino acids, and that could overwhelm the liver's capacity for ureagenesis. It's also possible that increases in phosphate utilization (or loss of phosphate in the urine, induced by the amino acids) decreases the availability of intracellular inorganic and organic phosphate in a way that impairs the activities of hepatic urea cycle enzymes. But one possibility that seems plausible to me is that amino acids increase urinary phosphate loss and that the loss of phosphate increases renal ammoniagenesis to a degree that is significant enough to disturb the systemic acid-base homeostatic mechanisms and actually contribute to hyperammonemia. Under some circumstances, the overall urea cycle activity is thought to be an important factor in influencing systemic acid-base homeostasis, and Haussinger et al. (1990) [cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/02/urea-cycle-renal-glutaminase-activity.html); Haussinger et al., 1990: ([Haussinger et al., 1990: (http://www.springerlink.com/content/l2vx314521367706/)] basically found that even mild liver dysfunction was associated with a failure of renal ammoniagenesis to downregulate in response to systemic metabolic alkalosis. So, in a normal person, glutamine supplementation might acutely increase serum bicarbonate or only increase it on some days, such as on a day of intense exercise (in response to acidosis), but massive doses of glutamine or other essential amino acids that increase renal glutamine availability (glutaminase and the glutamine cycle are important in the regulation of renal ammoniagenesis, in response to metabolic acidosis) could contribute to the persistently-alkalotic state that can occur even in compensated liver disease, as discussed by Haussinger et al. (1990).
It's worth noting that alkalosis doesn't just increase phosphate uptake into cells (it tends to decrease intracellular phosphate availability in the long-term or even short term, because the uptake into cells provides phosphate to some cells at the expense of others, given the usual, alkalosis-induced reduction in serum phosphate) but impairs the unloading of oxygen from hemoglobin in a "2,3-DPG-depletion-independent" manner. That's one reason why bicarbonate administration can be so disastrous in a person who is hypophosphatemic, as discussed in past postings. One would think that the alkalosis-induced uptake (it's thought to partially be a result of the alkalosis-induced activation of glycolytic enzymes) of phosphate would increase 2,3-DPG levels, but it tends to not be the case in hypophosphatemia. It might be that more 2,3-DPG is driven into skeletal muscle myocytes or other cells that are not red blood cells, or it might be that the 2,3-DPG-independent "impairment" in the unloading of oxygen from hemoglobin tends to offset any potential for an increase in 2,3-DPG formation to occur in response to the alkalosis-induced increase in phosphate uptake by red blood cells. In any case, an inappropriate and persistent increase in renal ammoniagenesis could cause an ammonia-mediated impairment of TCA cycle activity in proximal tubule cells, given that ammonia excesses are known to inhibit TCA cycle enzymes and other mitochondrial enzymes and to interfere with energy metabolism by all sorts of mechanisms. That metabolic toxicity could reduce phosphate reabsorption by proximal tubule cells and exacerbate phosphaturia. Some of these articles by Ambuhl and colleagues (http://scholar.google.com/scholar?hl=en&q=ambuhl+phosphate) look promising as sources of information on those types of mechanisms.
Sunday, September 6, 2009
Effects of Acidic vs. Neutral vs. Alkaline Phosphate Preparations on Urinary Calcium Excretion: Interactions With B6 & Glutamine & Insulin Metabolism
These articles [Thomas, 1978: (http://www.ncbi.nlm.nih.gov/pubmed/351267); Lau et al., 1979: (http://www.ncbi.nlm.nih.gov/pubmed/44888)] are really good, and Lau et al. (1979) found that the administration of alkaline phosphate preparations [salts of HPO4(2-)] to people who had hypercalciuria, due to either inappropriately-increased intestinal calcium absorption (absorptive hypercalciuria) or renal hypercalciuria (due to some problem originating in the kidneys and causing an excess of urinary calcium excretion), reduced the rate of urinary calcium excretion much more than neutral phosphate preparations or reductions in the subjects' dietary calcium intakes did. Thomas (1978) also noted that alkaline phosphate preparations but not acidic phosphates reduce urinary calcium and do only (or, probably, mainly) in people who are hypercalciuric. Lau et al. (1979) and Thomas (1978) also cited and discussed research showing that oral phosphate preparations increase pyrophosphate excretion and probably inhibit renal calcifications and stone formation, in part, by that mechanism. I don't know what the mechanism is thought to be for that effect, but it's conceivable that it occurs because inorganic phosphate, at concentrations found in vivo, can inhibit alkaline phosphatase activity (a high smooth-muscle-cell alkaline phosphatase activity tends to increase the risk of soft-tissue calcification by breaking down an inhibitor of calcification, namely pyrophosphate, into orthophosphate [HPO4(2-)], which can, at excessive concentrations, contribute to calcification) [Coburn et al., 1998: (http://jcem.endojournals.org/cgi/content/full/83/11/3951)(http://www.ncbi.nlm.nih.gov/pubmed/9814474?dopt=Abstract)]. A low alkaline phosphatase activity on the plasma membranes of various cell types or even in the serum could conceivably increase intracellular PLP, or coenzymated vitamin B6, and reduce extracellular or serum PLP levels, given that some minimal degree of alkaline phosphatase activity is required for cleavage of PLP and, hence, entry of B6 into cells, where it's rephosphorylated. So an excess of phosphate could conceivably cause B6 depletion by impairing B6 entry into cells, but Coburn et al. (1998) noted that phosphate depletion is more likely to reduce (intracellular) PLP levels by reducing the availability of phosphate for the phosphorylation of pyridoxal. It's not a technical statement and wouldn't necessarily be true, but maybe adequate amounts of dietary phosphate increase the ratio of pyrophosphate to orthophosphate in the extracellular fluid, etc. Many articles have shown that phosphate depletion tends to be accompanied by elevated serum alkaline phosphatase activity (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+%22alkaline+phosphatase%22), and that or tissue-restricted increases in alkaline phosphatase activity could occur in response to dietary phosphate depletion and, up to some point, above which the opposite effect could occur, increase the risk of soft-tissue calcification. I think there's some middle ground. The orthophosphates joined together in pyrophosphate have to come from somewhere. Also, Lau et al. (1979) found that neutral phosphate, in comparison to acidic phosphate [salts of H2PO4(-)], caused a lower rate of net acid excretion in the urine (and, not surprisingly, given that a major acidic species in urine is ammonium, caused a lower rate of ammonium excretion) and a higher rate of urinary citrate excretion. Urinary citrate is thought to protect against calcium phosphate or oxalate precipitation. One way of looking at the difference in acid excretion would be to say that more HPO4(2-) might have been available for protonation and excretion as H2PO4(-) in the group supplemented with neutral phosphate than in the acid phosphate group, thereby reducing renal ammoniagenesis and acid excretion as the ammonium ion [NH4(+)], but that's probably an overly-simplistic explanation.
Lewandowski and Rogers (2004) [Lewandowski and Rogers, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15232796)] found that 100 mg/day of vitamin B6 reduced urinary calcium, phosphorus (phosphate), and the amount of brushite "supersaturation" in relation to other forms of calcium phosphate crystals or amorphous aggregations. They also found that glutamine supplementation reduced "relative calcium oxalate supersaturation" in the urine, implying that it could help to reduce calcium oxalate stone formation, in theory. Maybe glutamine increased citrate excretion by acting as a precursor to citrate, given that researchers have shown that glutamine can increase the levels of intracellular and intramitochondrial citrate and other TCA cycle intermediates in various cell types. A higher urinary citrate is, as Lau et al. (1979) and others have noted, thought to be protective against calcium stone formation, and Cupisti et al. (2007) [Cupisti et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17184967)] found that insulin resistance was associated with a lower rate of urinary citrate excretion. I think 100 mg/day of vitamin B6 is too high as a long-term dosage of vitamin B6, mainly because of the risk of peripheral neuropathy, and 25-50 mg/day would, in my opinion, be a safer dose, in many cases, in the long term. The authors noted that vitamin B6 could have reduced urinary oxalate by increasing its metabolism (by PLP-dependent enzymes), and the authors didn't know why vitamin B6 had decreased urinary calcium excretion. It's mysterious, and I've discussed past research showing that vitamin B6 supplementation, in animals, can decrease serum calcium levels. That's not desirable, necessarily, when one looks at the many different effects, taken together, of vitamin B6. But there's probably some lower dosage that would be safer in the long term and that might produce some of the reductions in calcification of soft tissues (in addition to the antihypercalciuric effect that it could potentially have) that have also been associated with vitamin B6 supplementation (http://scholar.google.com/scholar?hl=en&q=calcification+%22vitamin+B6%22+OR+pyridoxine). Some of those articles are research on the use of magnesium to prevent calcification, and the authors appear to have just mentioned vitamin B6 or used it in combination with magnesium (MgO is magnesium oxide). Some authors have noted that excessive amounts of dietary phosphate could bind to calcium and thereby indirectly enhance urinary oxalate excretion, given that less oxalate in foods would bind to calcium in the gastrointestinal tract (more would be absorbed and then excreted in the urine). That could be important to remember, but who knows how much oxalate comes from foods or if the problem is more that the oxalate isn't being metabolized (or maybe too much is being formed, as a result of the metabolic syndrome, as suggested by the research of Cupisti et al. (2007), cited above). Sayer et al. (2004) [Sayer et al., 2004: (http://cs.portlandpress.com/cs/106/0549/1060549.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15027893)] was basically that, following some initial calcium oxalate precipitation (crystal formation), calcium phosphate can be more likely to precipitate and form mixed crystals, I guess, through "heterologous nucleation" (this must mean that there's a seeding effect of the calcium oxalate). Thus, vitamin B6 or glutamine (or whatever other factors that could reduce urinary oxalate supersaturation) could conceivably reduce urinary calcium phosphate deposition, in my opinion. Glutamine is probably not going to produce especially reliable effects, but I just think increases in glutamine availability (or maintenance of its availability) interacts favorably with the metabolic effects of inorganic phosphate, by multiple mechanisms.
Lewandowski and Rogers (2004) [Lewandowski and Rogers, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15232796)] found that 100 mg/day of vitamin B6 reduced urinary calcium, phosphorus (phosphate), and the amount of brushite "supersaturation" in relation to other forms of calcium phosphate crystals or amorphous aggregations. They also found that glutamine supplementation reduced "relative calcium oxalate supersaturation" in the urine, implying that it could help to reduce calcium oxalate stone formation, in theory. Maybe glutamine increased citrate excretion by acting as a precursor to citrate, given that researchers have shown that glutamine can increase the levels of intracellular and intramitochondrial citrate and other TCA cycle intermediates in various cell types. A higher urinary citrate is, as Lau et al. (1979) and others have noted, thought to be protective against calcium stone formation, and Cupisti et al. (2007) [Cupisti et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17184967)] found that insulin resistance was associated with a lower rate of urinary citrate excretion. I think 100 mg/day of vitamin B6 is too high as a long-term dosage of vitamin B6, mainly because of the risk of peripheral neuropathy, and 25-50 mg/day would, in my opinion, be a safer dose, in many cases, in the long term. The authors noted that vitamin B6 could have reduced urinary oxalate by increasing its metabolism (by PLP-dependent enzymes), and the authors didn't know why vitamin B6 had decreased urinary calcium excretion. It's mysterious, and I've discussed past research showing that vitamin B6 supplementation, in animals, can decrease serum calcium levels. That's not desirable, necessarily, when one looks at the many different effects, taken together, of vitamin B6. But there's probably some lower dosage that would be safer in the long term and that might produce some of the reductions in calcification of soft tissues (in addition to the antihypercalciuric effect that it could potentially have) that have also been associated with vitamin B6 supplementation (http://scholar.google.com/scholar?hl=en&q=calcification+%22vitamin+B6%22+OR+pyridoxine). Some of those articles are research on the use of magnesium to prevent calcification, and the authors appear to have just mentioned vitamin B6 or used it in combination with magnesium (MgO is magnesium oxide). Some authors have noted that excessive amounts of dietary phosphate could bind to calcium and thereby indirectly enhance urinary oxalate excretion, given that less oxalate in foods would bind to calcium in the gastrointestinal tract (more would be absorbed and then excreted in the urine). That could be important to remember, but who knows how much oxalate comes from foods or if the problem is more that the oxalate isn't being metabolized (or maybe too much is being formed, as a result of the metabolic syndrome, as suggested by the research of Cupisti et al. (2007), cited above). Sayer et al. (2004) [Sayer et al., 2004: (http://cs.portlandpress.com/cs/106/0549/1060549.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15027893)] was basically that, following some initial calcium oxalate precipitation (crystal formation), calcium phosphate can be more likely to precipitate and form mixed crystals, I guess, through "heterologous nucleation" (this must mean that there's a seeding effect of the calcium oxalate). Thus, vitamin B6 or glutamine (or whatever other factors that could reduce urinary oxalate supersaturation) could conceivably reduce urinary calcium phosphate deposition, in my opinion. Glutamine is probably not going to produce especially reliable effects, but I just think increases in glutamine availability (or maintenance of its availability) interacts favorably with the metabolic effects of inorganic phosphate, by multiple mechanisms.
Thursday, September 3, 2009
Royal Rambler on Vitamin D, Hypercalciuria, Phosphate, and Fairly Boring "Minerals"
The authors of this article [Hathcock et al., 2007: (http://www.ajcn.org/cgi/content/full/85/1/6)(http://www.ncbi.nlm.nih.gov/pubmed/17209171?dopt=Abstract)] reviewed a number of clinical trials in which researchers had used dosages of vitamin D ranging from 2,000-100,000 IU/day of vitamin D3, and the research generally shows that hypercalciuria hardly ever occurs at dosages of vitamin D3 of 2,000-4,000 IU/day. Hypercalcemia hardly occurred at any of the reasonable dosages and didn't even occur at 100,000 IU/day. There probably isn't a dose of vitamin D3 that has zero potential to elevate urinary calcium, and the slight elevations in serum calcium that oral vitamin D3, in particular, tends to cause (in my opinion) have the potential to exacerbate thrombogenic conditions, as discussed in past postings (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html).
Sayer et al. (2004) [Sayer, 2004: (http://cs.portlandpress.com/cs/106/0549/1060549.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15027893)] analyzed a lot of research on the mechanisms underlying nephrocalcinosis, which technically refers to an increase in the calcium contents of the kidneys but is generally taken to mean calcification, meaning the deposition of calcium phosphate (usually in the form of apatite), in parts of the kidneys, and Sayer et al. (2004) basically argued that hypercalciuria is the factor that seems to be associated with nephrocalcinosis. Even relatively small increases in the intake of phosphate have generally decreased the rate of urinary calcium excretion, and phosphate (from sodium or potassium phosphate) at something like 1,000 mg/day has been used to prevent kidney stones in recent decades. Then I guess everyone decided that phosphate is a "vice" or something and had to be removed from the diets of everyone. The research that I've discussed in recent postings indicates that taking very high dosages of phosphate (generally supplemental phosphate at greater than 70-100 mg/kg/day), along with hormonal vitamin D at dosages that cause intermittent hypercalcemia and hypercalciuria, creates the conditions that can cause nephrocalcinosis. But vitamin D itself generally does not cause either hypercalciuria or hypercalcemia, and there's some moderate dosage (i.e. 2,000-4,000 IU/day, as a conservative dosage) that could help keep the parathyroid hormone levels low but could do so without elevating urinary calcium unnecessarily. There's likely to be some middle ground, in my opinion.
One approach would be to use adequate dosages of magnesium (the research is really disorganized in magnesium, and that's the reason I keep avoiding citing all the articles I have on it), given that magnesium has the potential to help prevent nephrocalcinosis (http://scholar.google.com/scholar?hl=en&q=magnesium+nephrocalcinosis), in my opinion, and avoid calcium supplements and get calcium from milk or something like that. (There's some research claiming to show that magnesium decreases apatite formation but increases amorphous calcium phosphate formation, which is not really dangerous, but the research in actual animals generally shows that urinary magnesium wasting, from any number of causes, and decreases in magnesium status/intakes can increase the risk of calcification, in the kidneys and other sites.) I don't take supplemental calcium anymore and get enough calcium from milk that I use to "eat cereal." But anyway, the dosage range of magnesium is large, and I don't really feel like getting into a discussion of it and then have to "wade" through the research. The research on magnesium is not reader-friendly, really, and is surprisingly complex. Magnesium oxide (MgO) is absorbed relatively slowly, throughout much of the small intestine, and chelated magnesium aspartate (MgAsp) or MgAsp HCl (they're not the same) are absorbed more rapidly and are probably absorbed through either the amino acid or dipeptide transporters or by passive diffusion. Magnesium from magnesium oxide is likely to be absorbed by divalent metal transporters or by passive diffusion and the solvent drag mechanisms that enhance the absorption of some cations by passive diffusion. Some people report in the literature that the bioavailability of chelated MgAsp is basically too high for some people to be able to tolerate, and there might be something to that. If it enters the brain too rapidly, it can cause sort of drowsiness or mental sluggishness. The last time I tried chelated MgAsp, I experienced that sort of problem with it and went back to MgO. Some people can't tolerate MgO, however, at higher dosages, given the nausea and GI effects that it can cause. In that case, MgAsp might be preferable. Magnesium orotate would potentially be problematic, in my opinion, because of the orotate, as I discussed, indirectly, in one of my old papers (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html).
I've never seen a report of true toxicity from magnesium at anything resembling a reasonable dosage (even 1500-2000 mg/day have been used in some research), and the occasional reports of hypermagnesemia have generally occurred in people taking 2500-3000 mg/day or more. The intravenous magnesium dosages used in various therapeutic contexts produce really high serum magnesium levels, but any excess is likely to mainly end up being excreted in the urine almost immediately. There could be some problems with fasting blood glucose levels decreasing in diabetics, in response to Mg supplementation, and it can transiently lower blood pressure and elevate serum potassium (and decrease urinary sodium reabsorption). The changes in sodium and potassium excretion might produce the acute decreases in blood pressure, but, supposedly, the low-level calcium channel blocking effect can reduce blood pressure a little bit. But the blood pressure changes seem to not really persist to as great a degree as one might think. In people who are hypertensive, there might be more of a lasting effect, but I don't know that I'd expect much in that area. The research is sort of mixed on that, but there can be a transient decrease in blood pressure that does not last longer than a day or two, after any increase in the dosage. Obviously, one would want to talk about these things with one's doctor. Magnesium, like many things, could cause side effects (such as electrolyte abnormalities, etc.) that could be detrimental, in conjunction with the effects of medications, for example, but that would not really constitute toxicity, in my opinion, at reasonable dosages. Even in the cases of supposed death by magnesium dosages of 15,000-30,000 mg per day, the person had been drinking the whole bottle of the OTC magnesium supplement for a long time, in one case. And it wasn't clear to me that the existing kidney failure, not the bizarrely high dosages of magnesium, hadn't actually been the cause of death. Magnesium could conceivably increase phosphate turnover or the dietary phosphate requirement, either by binding to phosphate in the GI tract, thereby potentially increasing the requirement, or by increasing the activities of glycolytic enzymes. Reporting on the research on magnesium is like pulling teeth, though, because of the variable qualities of the bioavailabilities and even percent absorption of different magnesium salts or chelated forms. The only other thing I can think of to say is that magnesium aspartate may not mean chelated magnesium aspartate, depending on the manufacturer's labeling practices. Chelated MgAsp is not the same thing as MgAsp as a salt. In MgAsp, the Asp(2-) and Mg2+ are ionized. In chelated MgAsp, the Mg is bound to the aspartate by coordinate covalent bonds. A chelate tends to be absorbed (a significant percentage of a dosage) intact and transported by dipeptide or amino acid transporters or by passive diffusion, but a salt (an ionic pair in crystalline form that dissociates upon entry into solution) dissociates in water.
I should mention that I don't take a multivitamin, because of all of the potentially problematic "ingredients" in it. The only "minerals" or metals I take in supplemental form are selenium, from sodium selenite, at about 150 ug/day, 150 ug of iodine (from potassium iodide), magnesium, and a low dose of molybdenum. Iodine can basically shut down thyroid function at dosages slightly higher than the RDA of 150 ug/day, especially some people, and selenium can also decrease thyroid hormone levels (and cause obesity or something and decrease serum IGF-1 levels, etc.) at dosages of even 200-300 ug/day, according to some research [(http://scholar.google.com/scholar?q=selenium+thyroid+adverse&hl=en); Hawkes et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18565425)]. I can't get the articles showing IGF-1 decreases to show up, but one has to ask oneself what the mechanism would be for that. It doesn't sound like a good effect to me and doesn't sound like a great way of supposedly preventing cancer, but the decreases in IGF-1 may (or may not) only occur at the higher dosage range. But overt selenium deficiency (it's probably uncommon) can also decrease thyroid hormone formation. The function of selenium, in my opinion, is to serve as a cofactor of thioredoxin reductase enzyme complexes, glutaredoxin reductase enzyme(s), glutathione peroxidase enzymes, etc. (and ribonucleotide reductase). It seems like it can have relatively significant effects on antioxidant enzymes, but I'd suggest watching out for those adverse effects. The dosage that causes those effects in one person might be lower than the dosage that causes them in another person. One approach would be to stick to the low end of the range or evaluate how much selenium one gets from his or her diet Manganese is abundant in foods and has been shown to cause psychiatric and neurological derangements, when given in excess, in supplemental form. So I definitely don't supplement with that. Copper and zinc are very problematic in supplemental form, in my view, and are abundant in foods, and I don't take those. And then there's all the potentially neurotoxic or "choroid-plexus-epithelial-cell-toxic" vitamin A and beta-carotene in some multivitamins. I take a small amount of iron protein succinylate, because I work out like a @#$%&%$ madman. That's an exaggeration, but it's a bare-bones approach. In any case, I can't advise anyone on these more boring topics, even, or on any other topics. One would want to talk with one's doctor about these things.
Sayer et al. (2004) [Sayer, 2004: (http://cs.portlandpress.com/cs/106/0549/1060549.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15027893)] analyzed a lot of research on the mechanisms underlying nephrocalcinosis, which technically refers to an increase in the calcium contents of the kidneys but is generally taken to mean calcification, meaning the deposition of calcium phosphate (usually in the form of apatite), in parts of the kidneys, and Sayer et al. (2004) basically argued that hypercalciuria is the factor that seems to be associated with nephrocalcinosis. Even relatively small increases in the intake of phosphate have generally decreased the rate of urinary calcium excretion, and phosphate (from sodium or potassium phosphate) at something like 1,000 mg/day has been used to prevent kidney stones in recent decades. Then I guess everyone decided that phosphate is a "vice" or something and had to be removed from the diets of everyone. The research that I've discussed in recent postings indicates that taking very high dosages of phosphate (generally supplemental phosphate at greater than 70-100 mg/kg/day), along with hormonal vitamin D at dosages that cause intermittent hypercalcemia and hypercalciuria, creates the conditions that can cause nephrocalcinosis. But vitamin D itself generally does not cause either hypercalciuria or hypercalcemia, and there's some moderate dosage (i.e. 2,000-4,000 IU/day, as a conservative dosage) that could help keep the parathyroid hormone levels low but could do so without elevating urinary calcium unnecessarily. There's likely to be some middle ground, in my opinion.
One approach would be to use adequate dosages of magnesium (the research is really disorganized in magnesium, and that's the reason I keep avoiding citing all the articles I have on it), given that magnesium has the potential to help prevent nephrocalcinosis (http://scholar.google.com/scholar?hl=en&q=magnesium+nephrocalcinosis), in my opinion, and avoid calcium supplements and get calcium from milk or something like that. (There's some research claiming to show that magnesium decreases apatite formation but increases amorphous calcium phosphate formation, which is not really dangerous, but the research in actual animals generally shows that urinary magnesium wasting, from any number of causes, and decreases in magnesium status/intakes can increase the risk of calcification, in the kidneys and other sites.) I don't take supplemental calcium anymore and get enough calcium from milk that I use to "eat cereal." But anyway, the dosage range of magnesium is large, and I don't really feel like getting into a discussion of it and then have to "wade" through the research. The research on magnesium is not reader-friendly, really, and is surprisingly complex. Magnesium oxide (MgO) is absorbed relatively slowly, throughout much of the small intestine, and chelated magnesium aspartate (MgAsp) or MgAsp HCl (they're not the same) are absorbed more rapidly and are probably absorbed through either the amino acid or dipeptide transporters or by passive diffusion. Magnesium from magnesium oxide is likely to be absorbed by divalent metal transporters or by passive diffusion and the solvent drag mechanisms that enhance the absorption of some cations by passive diffusion. Some people report in the literature that the bioavailability of chelated MgAsp is basically too high for some people to be able to tolerate, and there might be something to that. If it enters the brain too rapidly, it can cause sort of drowsiness or mental sluggishness. The last time I tried chelated MgAsp, I experienced that sort of problem with it and went back to MgO. Some people can't tolerate MgO, however, at higher dosages, given the nausea and GI effects that it can cause. In that case, MgAsp might be preferable. Magnesium orotate would potentially be problematic, in my opinion, because of the orotate, as I discussed, indirectly, in one of my old papers (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html).
I've never seen a report of true toxicity from magnesium at anything resembling a reasonable dosage (even 1500-2000 mg/day have been used in some research), and the occasional reports of hypermagnesemia have generally occurred in people taking 2500-3000 mg/day or more. The intravenous magnesium dosages used in various therapeutic contexts produce really high serum magnesium levels, but any excess is likely to mainly end up being excreted in the urine almost immediately. There could be some problems with fasting blood glucose levels decreasing in diabetics, in response to Mg supplementation, and it can transiently lower blood pressure and elevate serum potassium (and decrease urinary sodium reabsorption). The changes in sodium and potassium excretion might produce the acute decreases in blood pressure, but, supposedly, the low-level calcium channel blocking effect can reduce blood pressure a little bit. But the blood pressure changes seem to not really persist to as great a degree as one might think. In people who are hypertensive, there might be more of a lasting effect, but I don't know that I'd expect much in that area. The research is sort of mixed on that, but there can be a transient decrease in blood pressure that does not last longer than a day or two, after any increase in the dosage. Obviously, one would want to talk about these things with one's doctor. Magnesium, like many things, could cause side effects (such as electrolyte abnormalities, etc.) that could be detrimental, in conjunction with the effects of medications, for example, but that would not really constitute toxicity, in my opinion, at reasonable dosages. Even in the cases of supposed death by magnesium dosages of 15,000-30,000 mg per day, the person had been drinking the whole bottle of the OTC magnesium supplement for a long time, in one case. And it wasn't clear to me that the existing kidney failure, not the bizarrely high dosages of magnesium, hadn't actually been the cause of death. Magnesium could conceivably increase phosphate turnover or the dietary phosphate requirement, either by binding to phosphate in the GI tract, thereby potentially increasing the requirement, or by increasing the activities of glycolytic enzymes. Reporting on the research on magnesium is like pulling teeth, though, because of the variable qualities of the bioavailabilities and even percent absorption of different magnesium salts or chelated forms. The only other thing I can think of to say is that magnesium aspartate may not mean chelated magnesium aspartate, depending on the manufacturer's labeling practices. Chelated MgAsp is not the same thing as MgAsp as a salt. In MgAsp, the Asp(2-) and Mg2+ are ionized. In chelated MgAsp, the Mg is bound to the aspartate by coordinate covalent bonds. A chelate tends to be absorbed (a significant percentage of a dosage) intact and transported by dipeptide or amino acid transporters or by passive diffusion, but a salt (an ionic pair in crystalline form that dissociates upon entry into solution) dissociates in water.
I should mention that I don't take a multivitamin, because of all of the potentially problematic "ingredients" in it. The only "minerals" or metals I take in supplemental form are selenium, from sodium selenite, at about 150 ug/day, 150 ug of iodine (from potassium iodide), magnesium, and a low dose of molybdenum. Iodine can basically shut down thyroid function at dosages slightly higher than the RDA of 150 ug/day, especially some people, and selenium can also decrease thyroid hormone levels (and cause obesity or something and decrease serum IGF-1 levels, etc.) at dosages of even 200-300 ug/day, according to some research [(http://scholar.google.com/scholar?q=selenium+thyroid+adverse&hl=en); Hawkes et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18565425)]. I can't get the articles showing IGF-1 decreases to show up, but one has to ask oneself what the mechanism would be for that. It doesn't sound like a good effect to me and doesn't sound like a great way of supposedly preventing cancer, but the decreases in IGF-1 may (or may not) only occur at the higher dosage range. But overt selenium deficiency (it's probably uncommon) can also decrease thyroid hormone formation. The function of selenium, in my opinion, is to serve as a cofactor of thioredoxin reductase enzyme complexes, glutaredoxin reductase enzyme(s), glutathione peroxidase enzymes, etc. (and ribonucleotide reductase). It seems like it can have relatively significant effects on antioxidant enzymes, but I'd suggest watching out for those adverse effects. The dosage that causes those effects in one person might be lower than the dosage that causes them in another person. One approach would be to stick to the low end of the range or evaluate how much selenium one gets from his or her diet Manganese is abundant in foods and has been shown to cause psychiatric and neurological derangements, when given in excess, in supplemental form. So I definitely don't supplement with that. Copper and zinc are very problematic in supplemental form, in my view, and are abundant in foods, and I don't take those. And then there's all the potentially neurotoxic or "choroid-plexus-epithelial-cell-toxic" vitamin A and beta-carotene in some multivitamins. I take a small amount of iron protein succinylate, because I work out like a @#$%&%$ madman. That's an exaggeration, but it's a bare-bones approach. In any case, I can't advise anyone on these more boring topics, even, or on any other topics. One would want to talk with one's doctor about these things.
Tuesday, September 1, 2009
Hypercalciuria and Nephrocalcinosis as Presenting Signs/Symptoms in HHRH: Potential Relevance to Phosphate Homeostasis in Normal People
In this article [Bergwitz et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1380228)(http://www.ncbi.nlm.nih.gov/pubmed/16358214)], Bergwitz et al. (2006) discussed the fact that nephrocalcinosis is often but not always a presenting symptom in hereditary hypophosphatemic rickets with hypercalciuria (HHRH). This is the third form of hypophosphatemia that I've read about and that results from mutations in nuclear DNA. In HHRH, there's hypofunctionality of one or another of the phosphate transporters that reabsorb filtered phosphate from the tubular fluid. The fact that nephrocalcinosis occurs before the people are ever treated with exogenous phosphate and occurs as a result of the phosphate depletion-induced elevations in calcitriol (1alpha,25-dihydroxyvitamin D, or 1,25-VD) provides some more indirect evidence that hypercalciuria is likely to contribute prominently to the nephrocalcinosis that can occur in people taking high doses of phosphate and hormonal vitamin D (or high doses of vitamin D) in combination [i.e. in X-linked hypophosphatemic rickets (XLHR) and autosomal dominant hypophosphatemic rickets]. Given that the physiological (endocrinological, etc.) conditions in HHRH are likely to, arguably, more closely mimic the conditions that would be present in a condition such as Fanconi syndrome (or even dietary phosphate depletion, to the extent that phosphate depletion could produce acidosis and mitochondrial damage in the proximal tubules), the research on HHRH suggests that the hypercalciuria that reliably accompanies significant dietary phosphate depletion (see past postings) (and the intracellular phosphate depletion that ultimately can result from it) could itself cause nephrocalcinosis.
In XLHR, part of the rationale for using calcitriol is to suppress the parathyroid hormone (PTH) release that can occur in response to the phosphate-induced decreases in serum calcium. In HHRH, there's no need to use calcitriol, because the serum calcium levels tend to be normal or elevated. And people who have HHRH display elevations in serum calcitriol levels, unless they're vitamin D deficient (severe but not mild vitamin D depletion decreases serum calcitriol, and vitamin D supplementation only increases serum calcitriol in people who are severely vitamin D deficient). The fact that normal vitamin D doesn't increase serum calcitriol past a certain point in normal people and can, at high dosages, actually decrease serum calcitriol (perhaps partly by increasing phosphate retention) is relevant to phosphate homeostasis in normal people. In my opinion, vitamin D (cholecalciferol, not calcitriol) at reasonable dosages (i.e. 2000-4000 IU/day or dosages that aren't high enough to potentially increase serum calcium and urinary calcium by much, if at all) could help to maintain low PTH levels in the context of reasonable increases in the dietary phosphate intake, in relation to the calcium intake. One reason it's desirable to maintain low serum PTH levels is that high PTH levels can increase urinary phosphate excretion and even, under extreme conditions, decrease the steady-state serum phosphate levels to a range that is below the baseline phosphate level (i.e. before the phosphate supplementation started). But that sort of derangement is more likely to occur, in my opinion, if one neglects magnesium homeostasis and doesn't take some reasonable but not massive amount of dietary calcium. I'm not much up for citing a bunch of articles today, but the point is that vitamin D can suppress PTH levels to a reasonable extent, much as calcitriol can [Barger-Lux et al., 1998: (http://scholar.google.com/scholar?hl=en&q=Barger-Lux+graded)], but can do so without the hypercalcemia and hypercalciuria that accompany calcitriol administration. Anyway, it's important to remember the potential that exists, in my view, for thrombogenic effects to result from even slight increases in serum calcium (such as in response to vitamin D, particularly orally-administered vitamin D) in people who have thrombogenic disorders or who are susceptible to that type of thing. Obviously, one would want to discuss this with one's doctor.
In XLHR, part of the rationale for using calcitriol is to suppress the parathyroid hormone (PTH) release that can occur in response to the phosphate-induced decreases in serum calcium. In HHRH, there's no need to use calcitriol, because the serum calcium levels tend to be normal or elevated. And people who have HHRH display elevations in serum calcitriol levels, unless they're vitamin D deficient (severe but not mild vitamin D depletion decreases serum calcitriol, and vitamin D supplementation only increases serum calcitriol in people who are severely vitamin D deficient). The fact that normal vitamin D doesn't increase serum calcitriol past a certain point in normal people and can, at high dosages, actually decrease serum calcitriol (perhaps partly by increasing phosphate retention) is relevant to phosphate homeostasis in normal people. In my opinion, vitamin D (cholecalciferol, not calcitriol) at reasonable dosages (i.e. 2000-4000 IU/day or dosages that aren't high enough to potentially increase serum calcium and urinary calcium by much, if at all) could help to maintain low PTH levels in the context of reasonable increases in the dietary phosphate intake, in relation to the calcium intake. One reason it's desirable to maintain low serum PTH levels is that high PTH levels can increase urinary phosphate excretion and even, under extreme conditions, decrease the steady-state serum phosphate levels to a range that is below the baseline phosphate level (i.e. before the phosphate supplementation started). But that sort of derangement is more likely to occur, in my opinion, if one neglects magnesium homeostasis and doesn't take some reasonable but not massive amount of dietary calcium. I'm not much up for citing a bunch of articles today, but the point is that vitamin D can suppress PTH levels to a reasonable extent, much as calcitriol can [Barger-Lux et al., 1998: (http://scholar.google.com/scholar?hl=en&q=Barger-Lux+graded)], but can do so without the hypercalcemia and hypercalciuria that accompany calcitriol administration. Anyway, it's important to remember the potential that exists, in my view, for thrombogenic effects to result from even slight increases in serum calcium (such as in response to vitamin D, particularly orally-administered vitamin D) in people who have thrombogenic disorders or who are susceptible to that type of thing. Obviously, one would want to discuss this with one's doctor.
Wednesday, August 26, 2009
Supplemental Phosphate (and Calcitriol) in Hereditary Forms of Hypophosphatemia: Potential Relevance to Phosphate Dosages & Responses in Normal Humans
This article [Reusz et al., 1990: (http://fetalneonatal.com/cgi/reprint/65/10/1125.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2248503)], along with other articles that describe the adverse effects or absence of adverse effects of different dosages of supplemental phosphate in people who have X-linked hypophosphatemic rickets (XLHR) (or autosomal dominant hypophosphatemic rickets), are likely to be relevant to an understanding of the risks (or lack thereof) of phosphate supplementation in humans who don't have genetic disorders. Sitara et al. (2004) [Sitara et al., 2004: (http://www.geocities.com/razzaquems/MatrixBiology.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15579309)] noted that the mechanisms underlying the hypophosphatemia in those two sets of genetic disorders are not perfectly understood, but the actions or serum levels of FGF-23 (fibroblast growth factor-23) are augmented in both sets of genetic disorders. The PHEX gene product is an endopeptidase, a protease enzyme, and mutations in that gene evidently are the root cause of XLHR and, among other phenotypic changes, serve to augment the actions of FGF-23 (http://scholar.google.com/scholar?q=phex+hypophosphatemia&hl=en). One could make the argument that the hyperphosphaturia in people who have those genetic disorders would cause those people to be at a lesser risk of developing ectopic calcification, as in response to any given dosage of supplemental phosphate. But I don't think that's true. Researchers have reported many cases of nephrocalcinosis, which is calcification of parts of the kidneys and would be the main risk of (particularly excessive) phosphate supplementation (in my opinion), in people with XLHR who have taken the combination of phosphate and hormonal vitamin D (HVD), which is calcitriol (1alpha,25-dihydroxyvitamin D3), that has been the standard therapeutic approach to treating the hypophosphatemia in those disorders. FGF-23, a protein that is "hyperfunctional" in these genetic forms of hypophosphatemia, decreases renal HVD formation and decreases phosphate reabsorption by proximal tubule epithelial cells. With regard to HVD formation, one could make the argument that the decreases in serum HVD, in many people who have these genetic disorders, would make the supplemental HVD less toxic than it would be in normal people, thereby confounding an attempt to sort through the risks of HVD vs. supplemental phosphate and to get a sense of the risks of different dosages of phosphate in normal people. But I don't think that's likely to be a valid reason for ignoring the data in some of these articles, either, because HVD seems to have been causing the same hypercalciuria and hypercalcemia in people with genetic hypophosphatemia as it tends to in normal humans.
The dosages of phosphate that have been associated with nephrocalcinosis in humans, as described by Reusz et al. (1990), are really high (a mean of 136.4 mg/kg bw/day, or 9548 mg/day, for a 70-kg human), and the "lower" range of dosages of phosphate (50-100 mg/kg bw/day, which is about 3500-7000 mg/day, or a mean of 69.9 mg/kg bw/day, which is 4893 mg/day) were not associated with nephrocalcinosis but were still quite high. Those dosages (more than 4000-5000 mg of phosphate/day, from any supplemental phosphate and food-derived phosphate, combined) are similar to the dosages that, for example, Heaney (2004) [Heaney, 2004: (http://www.mayoclinicproceedings.com/content/79/1/91.full.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/14708952)] was saying would potentially cause problems in humans. But almost no one ingests anywhere near those amounts of phosphate (which were, as discussed, not associated with nephrocalcinosis) per day, and a maximum of only 2300 mg/day of supplemental phosphate was required to treat people (who did not have genetic disorders) who displayed idiopathic (cause-unknown) phosphate depletion ("phosphate diabetes"). My point is that it's not a choice between the use of massive amounts of phosphate and the appalling consequences of the phosphate depletion that could occur, in the 21st century, here, in people who ingest only sources of "phytates," in whole grains and other vegetable- and plant-derived foods, that may provide little utilizable phosphate. There's a middle ground between the use of high doses of phosphate (and the state of blind terror, at the prospect of phosphate-induced nephrocalcinosis, that could go along with that) and the sense of "comfort in the majority viewpoint" that seems to potentially go along with phosphate deprivation and with the development of hypoxic brain injuries and osteomalacia and arthropathy (potentially, neuropathic, degenerative arthropathy/osteopathy) (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+osteopathy+OR+arthropathy) (it seems to me that the lower back pain and lumbar vertebral collapse/degeneration that characterize phosphate depletion are somewhat reminiscent of the neuropathic arthropathy seen in Charcot foot disease, for example, meaning that the symptoms and manifestations could be partially neuropathic in origin) that can result from intracellular phosphate depletion.
Also, Goodyer et al. (1987) [Goodyer et al., 1987: (http://www.ncbi.nlm.nih.gov/pubmed/2822887)] discussed the dosage range of HVD (40 ng/kg/day, or 2800 ng/day, for a 70-kg human) that had been associated with the development of nephrocalcinosis in people with XLHR or autosomal dominant hypophosphatemic rickets (ADHR), and researchers have generally used very high dosages of either vitamin D2, vitamin D3, and/or HVD in people who have had those disorders. Goodyer et al. (1987) supposedly found adverse effects associated with an intake of 4000 IU/day of vitamin D2 in people with XLHR or ADHR, but one wonders if, given all of the problems, reported in old articles, with vitamin D supplements containing ten times the labeled content of vitamin D, the dosage was actually higher. That dosage range (4000 IU/day) of vitamin D has not been reported to cause hypercalcemia in studies in normal humans. Another possibility is that the people were taking vitamin D and HVD and that the hypercalcemia was attributed to the vitamin D (as opposed to the HVD, which is the more likely culprit, in my opinion). I say that because I've never seen any case report in which a person with XLHR or ADHR was given, as a standalone treatment, only a low dosage of 4000 IU/day of vitamin D3 or vitamin D2. In most cases, the dosages have been massive, and hypercalciuria seems more likely to be a cause of the nephrocalcinosis than phosphate supplementation per se, in most of these people. Gross et al. (1998) [Gross et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9598513)] found that 2.5 ug HVD/day (2500 ng/day), in normal humans who had prostate cancer, caused hypercalciuria in everyone, at dosages ranging from 1500-2500 ng/day. Reisz et al. (1990) argued, despite the past research that had associated hypercalciuria with nephrocalcinosis and that they cited, that hypercalciuria had been associated more with the development of kidney stones than with the development of nephrocalcinosis, but, in most trials in people who have not had XLHR or ADHR, the participants have not taken both HVD and phosphate supplements, in massive dosages. The dosages of vitamin D (198-1370 IU/kg/day, or 13860-95900 IU/day) and HVD (5-35 ng/kg/day , or 350-2450 ng/day) are large and, perhaps not surprisingly, the people who displayed nephrocalcinosis had been the ones who had experienced multiple episodes of hypercalciuria or hypercalcemia. Nephrocalcinosis requires pathologically-increased concentrations of both calcium and phosphate, usually, to occur. Additionally, Seikaly et al. (1996) [Seikaly et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8545232)] found that nephrocalcinosis was more common in people who were taking HVD and phosphate and who had renal tubular acidosis. Metabolic acidosis, in the proximal tubule epithelial cells that reabsorb most of the phosphate from the tubular fluid, can cause urinary phosphate loss, but intracellular phosphate depletion can also be an important cause of metabolic acidosis. Thus, metabolic acidosis can be both a cause and a consequence of intracellular phosphate depletion, and it's important to remember these types of complexities. The insulin resistance and mitochondrial toxicity that can result from chronic phosphate depletion have the potential to actually increase the risk of calcification, because inorganic phosphate is constantly going to be "dumped" from its "storage" in intracellular phosphocreatine and adenosine nucleotide pools, etc. That's been suggested to be one mechanism for tissue-specific calcification in any number of disorders, in people who do not have XLHR. When there are these constant metabolic crises, such as can occur in response to intracellular phosphate depletion, there will tend to be these frequent, intermittent "episodes" in which phosphate is lost from cells or from its intracellular binding to organic compounds (such as creatine) and elevated, pathologically, in the extracellular or intracellular (cytosolic or mitochondrial) fluid. More specifically, for example, rhabdomyolysis is a fairly common result of intracellular phosphate depletion, and rhabdomyolysis can cause both wild elevations in serum phosphate (and, hence, phosphate concentrations in the kidneys, potentially contributing to nephrocalcinosis) and elevations in myoglobin and other proteins, released from necrotic muscle cells. Chronic rhabdomyolysis, such as in response to exercise in a person who is phosphate-depleted, has the potential to cause more kidney damage than phosphate supplementation ever would, and there are reports of people dying from rhabdomyolysis that was associated with (and likely to have been a consequence of, in my opinion) intracellular phosphate depletion in muscle cells and other cells (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+rhabdomyolysis+renal+failure).
Furthermore, "high" intakes of phosphate are well known to actually decrease urinary calcium excretion [Hegsted et al., 1981: (http://jn.nutrition.org/cgi/reprint/111/3/553.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7205408); LaFlamme and Jowsey, 1972: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=292432&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/5080411)], and the high urinary calcium excretion that accompanies phosphate depletion is thought to be due, in large part, to the ongoing breakdown of hydroxyapatite in the bone tissue [Laroche et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8358977)]. Incidentally, I scaled those dosages of phosphate that were given to dogs and that were associated with calcification, in the study by LaFlamme and Jowsey (1972), and the equivalent human dosages would be massive (I did the calculations awhile ago, and it works out to 8000-some mg/day or more of phosphate). I honestly don't understand what the problem is with those types of dosage considerations in research in animals. The disregard for the physiological norms, in the context of dosages of so many nutrients or compounds that are given to animals, is significant, in my opinion, and is an ongoing issue in animal research.
Incidentally, Laroche et al. (1993) discussed the neuropsychiatric and pain-related manifestations of intracellular phosphate depletion and also found that people who had phosphate diabetes (intracellular phosphate depletion) displayed symptoms consistent with reflex sympathetic dystrophy. That's a condition that's mysterious and that causes bizarre, extreme pain and other symptoms. I don't have time to go into all of that, but it's basically more evidence that neuropathy and neurological damage can sometimes be one manifestation of phosphate depletion, in my opinion (and is evidence that the "back pain" or "bone pain" of phosphate depletion may be neuropathic in origin and may not have to do with bone problems per se, independent of the central nervous system).
It's also important to remember that increases in the phosphate intake could bind magnesium in the GI tract and produce adverse effects by that mechanism. Supplemental magnesium could conceivably reduce some of the supposed risk of increases in the dietary phosphate/(Ca+Mg) intake ratio, in my opinion, although I can't make any guarantees, at all, about safety in individuals or even in general. All I can offer is my sense of things. Even though supplemental magnesium increases phosphate reabsorption in animals and can decrease parathyroid hormone release (magnesium only increases PTH levels, up to a point, when a person has been grossly deficient in magnesium) [Thumfart et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18701629)], magnesium has been shown to reduce the incidence or extent of calcification in animals taking massive amounts of phosphate. I'll collect some of those articles, but the point is that the use of supplemental magnesium is worthwhile, in my opinion, and is likely to be especially worthwhile in the context of an increase in the phosphate intake, from food or another source, in relation to the intakes of magnesium and calcium, etc. That said, one would want to monitor one's electrolytes and discuss these issues with one's doctor. Magnesium can elevate serum potassium and cause natriuresis (an increase in urinary sodium excretion) at high dosages, even though a high-magnesium diet (Thumfart et al., 2008) decreased urinary sodium loss in animals in that article.
The dosages of phosphate that have been associated with nephrocalcinosis in humans, as described by Reusz et al. (1990), are really high (a mean of 136.4 mg/kg bw/day, or 9548 mg/day, for a 70-kg human), and the "lower" range of dosages of phosphate (50-100 mg/kg bw/day, which is about 3500-7000 mg/day, or a mean of 69.9 mg/kg bw/day, which is 4893 mg/day) were not associated with nephrocalcinosis but were still quite high. Those dosages (more than 4000-5000 mg of phosphate/day, from any supplemental phosphate and food-derived phosphate, combined) are similar to the dosages that, for example, Heaney (2004) [Heaney, 2004: (http://www.mayoclinicproceedings.com/content/79/1/91.full.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/14708952)] was saying would potentially cause problems in humans. But almost no one ingests anywhere near those amounts of phosphate (which were, as discussed, not associated with nephrocalcinosis) per day, and a maximum of only 2300 mg/day of supplemental phosphate was required to treat people (who did not have genetic disorders) who displayed idiopathic (cause-unknown) phosphate depletion ("phosphate diabetes"). My point is that it's not a choice between the use of massive amounts of phosphate and the appalling consequences of the phosphate depletion that could occur, in the 21st century, here, in people who ingest only sources of "phytates," in whole grains and other vegetable- and plant-derived foods, that may provide little utilizable phosphate. There's a middle ground between the use of high doses of phosphate (and the state of blind terror, at the prospect of phosphate-induced nephrocalcinosis, that could go along with that) and the sense of "comfort in the majority viewpoint" that seems to potentially go along with phosphate deprivation and with the development of hypoxic brain injuries and osteomalacia and arthropathy (potentially, neuropathic, degenerative arthropathy/osteopathy) (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+osteopathy+OR+arthropathy) (it seems to me that the lower back pain and lumbar vertebral collapse/degeneration that characterize phosphate depletion are somewhat reminiscent of the neuropathic arthropathy seen in Charcot foot disease, for example, meaning that the symptoms and manifestations could be partially neuropathic in origin) that can result from intracellular phosphate depletion.
Also, Goodyer et al. (1987) [Goodyer et al., 1987: (http://www.ncbi.nlm.nih.gov/pubmed/2822887)] discussed the dosage range of HVD (40 ng/kg/day, or 2800 ng/day, for a 70-kg human) that had been associated with the development of nephrocalcinosis in people with XLHR or autosomal dominant hypophosphatemic rickets (ADHR), and researchers have generally used very high dosages of either vitamin D2, vitamin D3, and/or HVD in people who have had those disorders. Goodyer et al. (1987) supposedly found adverse effects associated with an intake of 4000 IU/day of vitamin D2 in people with XLHR or ADHR, but one wonders if, given all of the problems, reported in old articles, with vitamin D supplements containing ten times the labeled content of vitamin D, the dosage was actually higher. That dosage range (4000 IU/day) of vitamin D has not been reported to cause hypercalcemia in studies in normal humans. Another possibility is that the people were taking vitamin D and HVD and that the hypercalcemia was attributed to the vitamin D (as opposed to the HVD, which is the more likely culprit, in my opinion). I say that because I've never seen any case report in which a person with XLHR or ADHR was given, as a standalone treatment, only a low dosage of 4000 IU/day of vitamin D3 or vitamin D2. In most cases, the dosages have been massive, and hypercalciuria seems more likely to be a cause of the nephrocalcinosis than phosphate supplementation per se, in most of these people. Gross et al. (1998) [Gross et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9598513)] found that 2.5 ug HVD/day (2500 ng/day), in normal humans who had prostate cancer, caused hypercalciuria in everyone, at dosages ranging from 1500-2500 ng/day. Reisz et al. (1990) argued, despite the past research that had associated hypercalciuria with nephrocalcinosis and that they cited, that hypercalciuria had been associated more with the development of kidney stones than with the development of nephrocalcinosis, but, in most trials in people who have not had XLHR or ADHR, the participants have not taken both HVD and phosphate supplements, in massive dosages. The dosages of vitamin D (198-1370 IU/kg/day, or 13860-95900 IU/day) and HVD (5-35 ng/kg/day , or 350-2450 ng/day) are large and, perhaps not surprisingly, the people who displayed nephrocalcinosis had been the ones who had experienced multiple episodes of hypercalciuria or hypercalcemia. Nephrocalcinosis requires pathologically-increased concentrations of both calcium and phosphate, usually, to occur. Additionally, Seikaly et al. (1996) [Seikaly et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8545232)] found that nephrocalcinosis was more common in people who were taking HVD and phosphate and who had renal tubular acidosis. Metabolic acidosis, in the proximal tubule epithelial cells that reabsorb most of the phosphate from the tubular fluid, can cause urinary phosphate loss, but intracellular phosphate depletion can also be an important cause of metabolic acidosis. Thus, metabolic acidosis can be both a cause and a consequence of intracellular phosphate depletion, and it's important to remember these types of complexities. The insulin resistance and mitochondrial toxicity that can result from chronic phosphate depletion have the potential to actually increase the risk of calcification, because inorganic phosphate is constantly going to be "dumped" from its "storage" in intracellular phosphocreatine and adenosine nucleotide pools, etc. That's been suggested to be one mechanism for tissue-specific calcification in any number of disorders, in people who do not have XLHR. When there are these constant metabolic crises, such as can occur in response to intracellular phosphate depletion, there will tend to be these frequent, intermittent "episodes" in which phosphate is lost from cells or from its intracellular binding to organic compounds (such as creatine) and elevated, pathologically, in the extracellular or intracellular (cytosolic or mitochondrial) fluid. More specifically, for example, rhabdomyolysis is a fairly common result of intracellular phosphate depletion, and rhabdomyolysis can cause both wild elevations in serum phosphate (and, hence, phosphate concentrations in the kidneys, potentially contributing to nephrocalcinosis) and elevations in myoglobin and other proteins, released from necrotic muscle cells. Chronic rhabdomyolysis, such as in response to exercise in a person who is phosphate-depleted, has the potential to cause more kidney damage than phosphate supplementation ever would, and there are reports of people dying from rhabdomyolysis that was associated with (and likely to have been a consequence of, in my opinion) intracellular phosphate depletion in muscle cells and other cells (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+rhabdomyolysis+renal+failure).
Furthermore, "high" intakes of phosphate are well known to actually decrease urinary calcium excretion [Hegsted et al., 1981: (http://jn.nutrition.org/cgi/reprint/111/3/553.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7205408); LaFlamme and Jowsey, 1972: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=292432&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/5080411)], and the high urinary calcium excretion that accompanies phosphate depletion is thought to be due, in large part, to the ongoing breakdown of hydroxyapatite in the bone tissue [Laroche et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8358977)]. Incidentally, I scaled those dosages of phosphate that were given to dogs and that were associated with calcification, in the study by LaFlamme and Jowsey (1972), and the equivalent human dosages would be massive (I did the calculations awhile ago, and it works out to 8000-some mg/day or more of phosphate). I honestly don't understand what the problem is with those types of dosage considerations in research in animals. The disregard for the physiological norms, in the context of dosages of so many nutrients or compounds that are given to animals, is significant, in my opinion, and is an ongoing issue in animal research.
Incidentally, Laroche et al. (1993) discussed the neuropsychiatric and pain-related manifestations of intracellular phosphate depletion and also found that people who had phosphate diabetes (intracellular phosphate depletion) displayed symptoms consistent with reflex sympathetic dystrophy. That's a condition that's mysterious and that causes bizarre, extreme pain and other symptoms. I don't have time to go into all of that, but it's basically more evidence that neuropathy and neurological damage can sometimes be one manifestation of phosphate depletion, in my opinion (and is evidence that the "back pain" or "bone pain" of phosphate depletion may be neuropathic in origin and may not have to do with bone problems per se, independent of the central nervous system).
It's also important to remember that increases in the phosphate intake could bind magnesium in the GI tract and produce adverse effects by that mechanism. Supplemental magnesium could conceivably reduce some of the supposed risk of increases in the dietary phosphate/(Ca+Mg) intake ratio, in my opinion, although I can't make any guarantees, at all, about safety in individuals or even in general. All I can offer is my sense of things. Even though supplemental magnesium increases phosphate reabsorption in animals and can decrease parathyroid hormone release (magnesium only increases PTH levels, up to a point, when a person has been grossly deficient in magnesium) [Thumfart et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18701629)], magnesium has been shown to reduce the incidence or extent of calcification in animals taking massive amounts of phosphate. I'll collect some of those articles, but the point is that the use of supplemental magnesium is worthwhile, in my opinion, and is likely to be especially worthwhile in the context of an increase in the phosphate intake, from food or another source, in relation to the intakes of magnesium and calcium, etc. That said, one would want to monitor one's electrolytes and discuss these issues with one's doctor. Magnesium can elevate serum potassium and cause natriuresis (an increase in urinary sodium excretion) at high dosages, even though a high-magnesium diet (Thumfart et al., 2008) decreased urinary sodium loss in animals in that article.
Monday, July 27, 2009
Phytates (Inositol Hexaphosphate and Related Compounds), in Plant-Based Foods, as Poor Sources of Utilizable Phosphate
The authors of this article [Johnson and Tate, 1969: (http://article.pubs.nrc-cnrc.gc.ca/ppv/RPViewDoc?issn=1480-3291&volume=47&issue=1&startPage=63)], a poorly-chosen but adequate one, discuss the fact that phytates in grains and plants and plant proteins are inositol polyphosphates, and they're not digested effectively in non-ruminants (i.e. humans and non-cow mammals, etc.). Phytic acid is the major one, and it's just myo-inositol hexaphosphate, a.k.a. inositol hexakisphosphate. But some of the other "phytates" are just inositol phosphorylated at one or more different oxygens, etc. It's really astonishing to me that this issue isn't discussed more than it is (I've never seen discussions of the extremely low digestibility of phytates), even apart from any consideration of the importance of phosphate. Iqbal et al. (1994) [Iqbal et al., 1994: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1375699&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7959229)] discussed the fact that the phytase (inositol polyphopsphate phosphohydrolase) activity in the human stomach and small intestine is, as is known, not produced by any human enzyme with phytase activity but by yeast or bacterial phytases found in foods. This is a great article, in which Letcher et al. (2008) [Letcher et al., 2008: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18684107)(http://www.ncbi.nlm.nih.gov/pubmed/18684107)] discussed the fact that phytates are unlikely to be transported into cells to a significant extent, because, upon their absorption, the compounds would form complexes with calcium and other divalent cations that are very low in solubility, etc. Human cells can hydrolyze inositol polyphosphates, but maybe there's something about the orientations/conformations of the phosphate linkages that precludes their hydrolysis by human enzymes (inositol triphosphate and other inositol phosphates act as second messengers and exert other signalling functions, etc.). But Letcher et al. (2008) make it sound as if dietary phytates don't even yield much phosphate, assuming they're absorbed at all, because of poor uptake into cells. I found some articles showing that meat essentially provides much more nutritionally-available phosphate than plant protein sources (plant foods that provide phosphate in phytate compounds) do, and that's the sense I'm also getting from these articles. So the nutrition information on the "phoshorus" content (from phosphate) in a plant-protein-based food is potentially going to be essentially incorrect, given that little utilizable phosphate can be provided by phytate compounds. Lopez et al. (2002) [Lopez et al., 2002: (http://cat.inist.fr/?aModele=afficheN&cpsidt=13944404)] discussed research showing that 80 percent of the phosphorus in plants or seeds exists in phytate compounds. The authors of this article [Sandberg et al., 1987: (http://jn.nutrition.org/cgi/reprint/117/12/2061.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2826727)] found that 58 percent of phytate(s) were hydrolyzed to inositol pentaphosphates (IP5's) and IP4's and IP3's, and that makes it sound as if microbial phytase activity can release variable amounts of phosphate. But one has to consider the fact that the IP5's or IP4's might just bind to divalent cations and precipitate, etc. And even the phytates that are absorbed by paracellular diffusion (many compounds can be absorbed by passive diffusion, to a larger extent than most articles imply or state) are not likely to yield much utilizable phosphate and may very well just be excreted in the urine (Letcher et al., 2008), etc.
That research is important, given that phosphate depletion could contribute to osteomalacia (see article, in the previous posting, on the capacity of calcium supplementation to bind phosphate in the GI tract and contribute to osteomalacia by inducing phosphate depletion) and all sorts of other problems, over time (see previous postings). I'm not even suggesting that eating meat protein and obtaining phosphate from meats is desirable or undesirable. I'm just trying to get a handle on what the actual amounts of utilizable phosphate are in different food groups.
That research is important, given that phosphate depletion could contribute to osteomalacia (see article, in the previous posting, on the capacity of calcium supplementation to bind phosphate in the GI tract and contribute to osteomalacia by inducing phosphate depletion) and all sorts of other problems, over time (see previous postings). I'm not even suggesting that eating meat protein and obtaining phosphate from meats is desirable or undesirable. I'm just trying to get a handle on what the actual amounts of utilizable phosphate are in different food groups.
Sunday, June 28, 2009
A Glimmer of Clarity and Understanding About the Significance of Serum Alkaline Phosphatase, in Relation to Vitamin B6 and Vitamin D
This is a complex and difficult-to-understand area of research, for various reasons, but some of these articles have helped me to sort of understand the alkaline phosphatase issue. The authors of this article [Lomashvili et al., 2004: (http://jasn.asnjournals.org/cgi/content/full/15/6/1392)(http://www.ncbi.nlm.nih.gov/pubmed/15153550?dopt=Abstract)] discuss evidence that elevated alkaline phosphatase activity, either on the plasma membranes of smooth muscle cells or in soluble form, apparently, in the plasma, hydrolyzes pyrophosphate (P03-O-PO3)(4-) (PPi) and thereby prevents the inhibition of vascular calcification that PPi is thought to confer, even in the presence of elevated levels of free calcium Ca2+ and inorganic PO4(3-) (PO4). Vitamin B6 repletion/supplementation and vitamin D3 repletion generally decrease serum alkaline phosphatase (ALP) and may reduce calcification, in part, by those mechanisms (to the extent that reductions in free ALP activity reflect some changes at the sites of calcification). Matias et al. (2009) [Matias et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/18775809?dopt=Abstract)], for example, found that 25-hydroxyvitamin D concentrations correlated inversely with the extents of vascular calcification among patients with renal failure. The PPI is thought to bind to sites of existing calcification and block PO4 from binding and forming more hydroxyapatite crystals. I cited some of the articles showing the vitamin B6 associations and mechanisms, in relation to ALP, in some past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/another-article-mentioning-plp-in.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html)].
This is a really confusing area of research, and it's still not clear to me what the origin of serum ALP is. Supposedly serum ALP decreases as bone turnover decreases, and Regidor et al. (2008) [Regidor et al., 2008: (http://www.asn-online.org/press/pdf/2008-Media/Kalantar-Zadeh-Bone%20Disease%20Study.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18667733)] discussed the fact that extreme and pathological decreases in bone turnover (such as might result from some of the osteoclast-and-monocyte-macrophage-lineage-cell-cytotoxic approaches to treating bone demineralization) can decrease serum ALP to pathologically low levels. I don't think those kinds of decreases would occur in response to reasonable dosages of supplemental vitamin D, but the increases in serum calcium that tend to result from either excessive vitamin D or calcium supplementation could, in my opinion, promote thrombogenic effects (hypercoagulability, etc.) (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html). The article by Seelig (1990) is especially good, and here are two articles that discuss those issues and that are cited in that old posting [Ruttmann et al., 2007:(http://www.anesthesiaanalgesia.org/cgi/content/full/104/6/1475) (http://www.ncbi.nlm.nih.gov/pubmed/17513645); Seelig, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2132751)]. Supposedly the actual serum ALP activity is partially a result of ALP, which acts extracellularly, on the plasma membranes of neutrophils, etc. I just read through an editorial and a couple of articles on ALP and calcification, and the researchers talk about the way no one really understands research on ALP. They don't say that, but they discuss the fact that it's not entirely clear if it's active on neutrophils or other cell types and then cleaved into a soluble form or what is even going on. It sounds like serum ALP is sort of like serum soluble transferrin receptor (sTfR), in the sense that serum ALP is normally produced, released upon cleavage of the membrane-anchored form during apoptosis (?), at some rate that correlates with the rate of turnover of osteoclasts and osteoblasts. But it can be elevated in cholestatic liver disease also (see 2nd old posting on vitamin B6 and ALP), etc. I guess this one article that I don't have time to cite right now says that serum ALP is enzymatically active but doesn't contribute to PPi cleavage. The authors also say that serum ALP don't correlate with serum PPi and that it's mainly the ALP expressed by smooth muscle cells that hydrolyzes PPi locally and is thought to thereby contribute to calcification (by forming PO4 locally, from PPi). The authors say no one knows why vascular calcification nonetheless seems to correlate with changes in bone turnover. I'm not sure what the correlation is that they're referring to, but presumably they're saying that increases in calcification accompany extremely low levels of bone turnover (presumably as a result of localized decreases in extracellular PPi at sites of vascular calcification, if one accepts the validity of these associations and mechanisms). They're saying they don't know how the expression and activity of smooth-muscle-cell ALP could be changed in association with changes in osteoblast apoptosis (and with the associated changes in serum ALP that do not contribute significantly to the localized cleavage of PPi, on the plasma membranes of the smooth muscle cells).
The research on vitamin B6 and ALP is just really confusing to everyone who reads it, seemingly, and to me. I can understand the basics--that plasma-membrane ALP cleaves albumin-bound pyridoxal-5'-phosphate (PLP) into pyridoxal, which then enters cells and is rephosphorylated, to PLP, by pyridoxal kinase. Humans and animals that have genetic mutations that decrease the activities of one or more of their alkaline phosphatase isoforms apparently have elevated serum PLP levels but have functional B6 deficiency, because ALP is required for the uptake of pyridoxal into cells (as discussed above). But it's not at all clear to me what the mechanism is by which an increase in B6 intake would decrease serum ALP. It's not an especially enjoyable topic to read about. I also think that excesses of B6 could produce neuropathy, in part, by decreasing ALP excessively, but that's just my opinion. And excesses of vitamin D intake could promote vascular calcification by elevating serum calcium, given that the traditional focus on the [Ca] x [PO4] product, as a factor whose elevation is associated with an increase in the extent calcification, shouldn't just be completely discounted or ignored. Everyone still seems to think taking a lot of calcium supplementation, beyond the RDA or whatever, is a good idea. I don't think it is, and I think people don't realize the manifold factors that can prevent the absorption or retention of dietary magnesium. I've discussed some of them in past postings and have discussed some of the dosage ranges that have been applied to extreme states, such as liver disease, in which magnesium absorption can become compromised. The dosage range for magnesium is fairly large, and I don't know what the right dosage is. That's the type of thing one would want to discuss with one's doctor.
This is a really confusing area of research, and it's still not clear to me what the origin of serum ALP is. Supposedly serum ALP decreases as bone turnover decreases, and Regidor et al. (2008) [Regidor et al., 2008: (http://www.asn-online.org/press/pdf/2008-Media/Kalantar-Zadeh-Bone%20Disease%20Study.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18667733)] discussed the fact that extreme and pathological decreases in bone turnover (such as might result from some of the osteoclast-and-monocyte-macrophage-lineage-cell-cytotoxic approaches to treating bone demineralization) can decrease serum ALP to pathologically low levels. I don't think those kinds of decreases would occur in response to reasonable dosages of supplemental vitamin D, but the increases in serum calcium that tend to result from either excessive vitamin D or calcium supplementation could, in my opinion, promote thrombogenic effects (hypercoagulability, etc.) (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html). The article by Seelig (1990) is especially good, and here are two articles that discuss those issues and that are cited in that old posting [Ruttmann et al., 2007:(http://www.anesthesiaanalgesia.org/cgi/content/full/104/6/1475) (http://www.ncbi.nlm.nih.gov/pubmed/17513645); Seelig, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2132751)]. Supposedly the actual serum ALP activity is partially a result of ALP, which acts extracellularly, on the plasma membranes of neutrophils, etc. I just read through an editorial and a couple of articles on ALP and calcification, and the researchers talk about the way no one really understands research on ALP. They don't say that, but they discuss the fact that it's not entirely clear if it's active on neutrophils or other cell types and then cleaved into a soluble form or what is even going on. It sounds like serum ALP is sort of like serum soluble transferrin receptor (sTfR), in the sense that serum ALP is normally produced, released upon cleavage of the membrane-anchored form during apoptosis (?), at some rate that correlates with the rate of turnover of osteoclasts and osteoblasts. But it can be elevated in cholestatic liver disease also (see 2nd old posting on vitamin B6 and ALP), etc. I guess this one article that I don't have time to cite right now says that serum ALP is enzymatically active but doesn't contribute to PPi cleavage. The authors also say that serum ALP don't correlate with serum PPi and that it's mainly the ALP expressed by smooth muscle cells that hydrolyzes PPi locally and is thought to thereby contribute to calcification (by forming PO4 locally, from PPi). The authors say no one knows why vascular calcification nonetheless seems to correlate with changes in bone turnover. I'm not sure what the correlation is that they're referring to, but presumably they're saying that increases in calcification accompany extremely low levels of bone turnover (presumably as a result of localized decreases in extracellular PPi at sites of vascular calcification, if one accepts the validity of these associations and mechanisms). They're saying they don't know how the expression and activity of smooth-muscle-cell ALP could be changed in association with changes in osteoblast apoptosis (and with the associated changes in serum ALP that do not contribute significantly to the localized cleavage of PPi, on the plasma membranes of the smooth muscle cells).
The research on vitamin B6 and ALP is just really confusing to everyone who reads it, seemingly, and to me. I can understand the basics--that plasma-membrane ALP cleaves albumin-bound pyridoxal-5'-phosphate (PLP) into pyridoxal, which then enters cells and is rephosphorylated, to PLP, by pyridoxal kinase. Humans and animals that have genetic mutations that decrease the activities of one or more of their alkaline phosphatase isoforms apparently have elevated serum PLP levels but have functional B6 deficiency, because ALP is required for the uptake of pyridoxal into cells (as discussed above). But it's not at all clear to me what the mechanism is by which an increase in B6 intake would decrease serum ALP. It's not an especially enjoyable topic to read about. I also think that excesses of B6 could produce neuropathy, in part, by decreasing ALP excessively, but that's just my opinion. And excesses of vitamin D intake could promote vascular calcification by elevating serum calcium, given that the traditional focus on the [Ca] x [PO4] product, as a factor whose elevation is associated with an increase in the extent calcification, shouldn't just be completely discounted or ignored. Everyone still seems to think taking a lot of calcium supplementation, beyond the RDA or whatever, is a good idea. I don't think it is, and I think people don't realize the manifold factors that can prevent the absorption or retention of dietary magnesium. I've discussed some of them in past postings and have discussed some of the dosage ranges that have been applied to extreme states, such as liver disease, in which magnesium absorption can become compromised. The dosage range for magnesium is fairly large, and I don't know what the right dosage is. That's the type of thing one would want to discuss with one's doctor.
Tuesday, June 9, 2009
Resistance Exercise vs. Endurance Exercise: Different Effects on AMPK and mTOR Activities
This article [Atherton et al., 2005: (http://www.fasebj.org/cgi/content/full/19/7/786)(http://www.ncbi.nlm.nih.gov/pubmed/15716393?dopt=Abstract)] shows that the high-frequency stimulation of muscles, which supposedly mimics the effects of resistance exercise, does not predominantly activate the often-discussed AMPK-PGC-1alpha pathway but instead leads to increases in protein synthesis by activating the mTOR pathway, by first activating protein kinase B. In contrast, the authors used low-frequency stimulation of muscles to reproduce the effects of endurance exercise, and this did activate the largely-catabolic AMPK-PGC-1alpha pathway that leads to mitochondrial proliferation. One could find fault with the experimental methods, but the findings of the article are very much consistent with my sense of the stark differences between the effects of resistance exercise/strength training and the effects of endurance exercise. There's a lot of other research showing that the activity of mammalian target of rapamycin enzyme(mTOR), a serine-threonine kinase, is negatively regulated by AMPK and hence by the increase in the AMP/ATP ratio [Roe et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16763896)] that tends to occur as a result of endurance exercise. Resistance exercise can also lead to an increase in AMPK activation in the short term, but the long-term effects are quite different from those of endurance exercise. The point is that cell growth, as discussed by Atherton et al. (2005), does not occur in response to the same intracellular conditions (or in response to the same stimuli) as mitochondrial proliferation ("biogenesis") occurs under.
HMB (3-hydroxyisovalerate) increases the phosphorylation and activity of mTOR, by an unknown mechanism [one of multiple articles showing this: Eley et al., 2007: (http://ajpendo.physiology.org/cgi/content/full/293/4/E923)(http://www.ncbi.nlm.nih.gov/pubmed/17609254)], but that's mainly interesting because HMB seems to act, largely or partly, by increasing the plasma membrane or intracellular cholesterol concentration in myocytes and other cell types. It's possible that it's more of a ketogenic substrate than a cholesterol "precursor," given that leucine is known to be ketogenic in astrocytes and hepatocytes and other cell types. I'm not that interested in HMB, because, in my opinion, the potential for problems with phosphate and calcium homeostasis, as a result of calcium salts of HMB that have to include added phosphate, etc., is not a great thing. But it would be interesting to know what the mechanism would be for the increase in mTOR activity in response to HMB. I guess some of the in vitro research would tend to argue against ketogenesis as a primary mechanism, but I would expect that to be one mechanism in vivo. I've suggested other mechanisms in past postings (acylation of proteins or histones by 3-hydroxyisovaleryl-CoA, etc.), but it seems as if the cellular cholesterol concentration might regulate AMPK by some mechanism in extrahepatic cell types. Or it might be that HMB decreases AMPK activity and thereby increase cholesterol biosynthesis, in addition to its role as an HMG-CoA precursor. Alternatively (but not by a mutually-exlusive mechanism), HMB might increase the cellular cholesterol levels in myocytes and, as a result of the feedback inhibition of HMG-CoA reductase activity by that cholesterol, spare acetyl-CoA for entry into the TCA cycle, etc.
HMB (3-hydroxyisovalerate) increases the phosphorylation and activity of mTOR, by an unknown mechanism [one of multiple articles showing this: Eley et al., 2007: (http://ajpendo.physiology.org/cgi/content/full/293/4/E923)(http://www.ncbi.nlm.nih.gov/pubmed/17609254)], but that's mainly interesting because HMB seems to act, largely or partly, by increasing the plasma membrane or intracellular cholesterol concentration in myocytes and other cell types. It's possible that it's more of a ketogenic substrate than a cholesterol "precursor," given that leucine is known to be ketogenic in astrocytes and hepatocytes and other cell types. I'm not that interested in HMB, because, in my opinion, the potential for problems with phosphate and calcium homeostasis, as a result of calcium salts of HMB that have to include added phosphate, etc., is not a great thing. But it would be interesting to know what the mechanism would be for the increase in mTOR activity in response to HMB. I guess some of the in vitro research would tend to argue against ketogenesis as a primary mechanism, but I would expect that to be one mechanism in vivo. I've suggested other mechanisms in past postings (acylation of proteins or histones by 3-hydroxyisovaleryl-CoA, etc.), but it seems as if the cellular cholesterol concentration might regulate AMPK by some mechanism in extrahepatic cell types. Or it might be that HMB decreases AMPK activity and thereby increase cholesterol biosynthesis, in addition to its role as an HMG-CoA precursor. Alternatively (but not by a mutually-exlusive mechanism), HMB might increase the cellular cholesterol levels in myocytes and, as a result of the feedback inhibition of HMG-CoA reductase activity by that cholesterol, spare acetyl-CoA for entry into the TCA cycle, etc.
Friday, May 29, 2009
Neuroprotective and Supposed Antidepressant-Like Effects of Sodium Butyrate: Relevance to HMB Research and Energy Metabolism
A lot of these articles showing that butyrate (usually administered or used in vitro as sodium butyrate, or SB), a short-chain fatty acid similar in structure to HMB (3-hydroxy-3-methylbutyrate or 3-hydroxyisovalerate, discussed in the two previous postings), reduces the degradation of numerous proteins by proteasomes are relevant to research on HMB. There are many similarities among the effects of butyrate and HMB. HMB is thought to exert its anticatabolic effects by inhibiting proteasomal activity (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=proteasome+methylbutyrate+OR+%223-hydroxyisovalerate%22) and also by acting as a precursor of HMG-CoA and of cholesterol. The extent to which an HMB-induced increase in cholesterol formation contributes to the HMB-induced inhibition of proteasomal activity is unknown. SB is a nonselective inhibitor of histone deacetylase enzymes in vitro, and its histone deacetylase inhibitory effect, at least in vitro, is thought to contribute to its inhibition of TNF-alpha-induced NFkappaB (NFkB) transcription factor [a.k.a. the "Rel" family of subunits that form the dimers that comprise NFkB transcription factors: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=RelA+RelB)] activation in the cytosol (Yin et al., 2001: (http://www.jbc.org/cgi/reprint/276/48/44641)(http://www.ncbi.nlm.nih.gov/pubmed/11572859?dopt=Abstract); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22sodium+butyrate%22+proteasome)]. Butyrate doesn't prevent the ubiquitination of IkB proteins (inhibitors of NFkB activation) but causes them to acccumulate as ubiquitin-conjugated proteins, without being degraded in proteasomes, evidently (Yin et al., 2001). HMB is also thought to exert anti-inflammatory effects by suppressing NFkB activation, as a result of the HMB-induced suppression of "proteasomal activity" [Baxter et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16006030)].
I don't doubt that some of those mechanisms are important, and a decrease in the activation of NFkB transcription factors can be antiproliferative and can downregulate the expression of numerous pro-inflammatory cytokines (cytokines that suppress mitochondrial functioning), etc., but SB is produced by microorganisms in the GI tract and is known to be the major energy substrate for colonocytes in the submucosal layers (I forget the terminology) of the colon (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22sodium+butyrate%22+energy). The in vitro research probably uses bizarre conditions and shows that SB can induce apoptosis of colon cancer cells. It looks like SB is pro-apoptotic at high but not low concentrations (0.5 mM to 2 mM) [Singh et al., 1997: (http://carcin.oxfordjournals.org/cgi/reprint/18/6/1265.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9214612)]. But SB supposedly doesn't produce very strong histone deacetylase inhibition in the brain in vivo in animals, but it does produce neuroprotective effects in all sorts of different models (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22sodium+butyrate%22+neurodegenerative+OR+neurological+OR+neuroprotective+OR+Parkinson%27s+OR+Huntington%27s+OR+ischemia+OR+ischaemia+OR+hypoxia+OR+anoxia). Sodium butyrate has also produced some "antidepressant-like" effects in animal models of depression (http://scholar.google.com/scholar?q=%22sodium+butyrate%22+antidepressant&hl=en&lr=). Sodium butyrate is also sold as a supplement (http://www.google.com/products?q=sodium+butyrate&hl=en&aq=f).
Anyway, I just put this information up here, but I have no idea what the dosage range would be. One would obviously want to discuss this type of thing with one's doctor, and the most obvious, potential problem would be the disturbances in phosphate or calcium homeostasis in response to something like this. The infusion of 3-hydroxybutyrate, a "ketone" that doesn't have a carbonyl group but is defined as being a ketone, and acetate, for example, can increase plasma bicarbonate, and this effect appears to be the result of the metabolism of the organic acids/fatty acids and not from effects on phosphate homeostasis, in some articles. But these organic anions can just have strange effects, and it's something to be aware. Many medications can affect acid-base homeostasis and could interact with sodium butyrate or HMB. Some anticonvulsants act as carbonic anhydrase inhibitors, for example, and could interact with these types of short-chain fatty acids (such as sodium butyrate) or branched-chain organic acids/fatty acids (such as HMB).
In my opinion, sodium butyrate probably acts mostly as an energy substrate, but that doesn't exclude other mechanisms. I also think the research on sodium butyrate is likely to be relevant to future research on the mechanisms of action of HMB. Both compounds inhibit proteasomal activity and may have overlapping or similar effects, but I don't think it's going to be as simple as testing HMB as a "histone deacetylase inhibitor." Histone acetylation is extraordinarily complex and dynamic, and to think that one can treat a multitude of conditions with histone deacetylase inhibitors is not realistic, in my opinion. Vitamin D receptor activation can increase histone acetylation (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22vitamin+D%22+histone+acetyltransferase+OR+acetylation), much as sodium butyrate supposedly does (histone deacetylase inhibition leads to increases in the acetylation of histone proteins). But it's clear, in my opinion, that a lot of the effects of sodium butyrate cannot be explained in terms of histone acetylation.
I don't doubt that some of those mechanisms are important, and a decrease in the activation of NFkB transcription factors can be antiproliferative and can downregulate the expression of numerous pro-inflammatory cytokines (cytokines that suppress mitochondrial functioning), etc., but SB is produced by microorganisms in the GI tract and is known to be the major energy substrate for colonocytes in the submucosal layers (I forget the terminology) of the colon (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22sodium+butyrate%22+energy). The in vitro research probably uses bizarre conditions and shows that SB can induce apoptosis of colon cancer cells. It looks like SB is pro-apoptotic at high but not low concentrations (0.5 mM to 2 mM) [Singh et al., 1997: (http://carcin.oxfordjournals.org/cgi/reprint/18/6/1265.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9214612)]. But SB supposedly doesn't produce very strong histone deacetylase inhibition in the brain in vivo in animals, but it does produce neuroprotective effects in all sorts of different models (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22sodium+butyrate%22+neurodegenerative+OR+neurological+OR+neuroprotective+OR+Parkinson%27s+OR+Huntington%27s+OR+ischemia+OR+ischaemia+OR+hypoxia+OR+anoxia). Sodium butyrate has also produced some "antidepressant-like" effects in animal models of depression (http://scholar.google.com/scholar?q=%22sodium+butyrate%22+antidepressant&hl=en&lr=). Sodium butyrate is also sold as a supplement (http://www.google.com/products?q=sodium+butyrate&hl=en&aq=f).
Anyway, I just put this information up here, but I have no idea what the dosage range would be. One would obviously want to discuss this type of thing with one's doctor, and the most obvious, potential problem would be the disturbances in phosphate or calcium homeostasis in response to something like this. The infusion of 3-hydroxybutyrate, a "ketone" that doesn't have a carbonyl group but is defined as being a ketone, and acetate, for example, can increase plasma bicarbonate, and this effect appears to be the result of the metabolism of the organic acids/fatty acids and not from effects on phosphate homeostasis, in some articles. But these organic anions can just have strange effects, and it's something to be aware. Many medications can affect acid-base homeostasis and could interact with sodium butyrate or HMB. Some anticonvulsants act as carbonic anhydrase inhibitors, for example, and could interact with these types of short-chain fatty acids (such as sodium butyrate) or branched-chain organic acids/fatty acids (such as HMB).
In my opinion, sodium butyrate probably acts mostly as an energy substrate, but that doesn't exclude other mechanisms. I also think the research on sodium butyrate is likely to be relevant to future research on the mechanisms of action of HMB. Both compounds inhibit proteasomal activity and may have overlapping or similar effects, but I don't think it's going to be as simple as testing HMB as a "histone deacetylase inhibitor." Histone acetylation is extraordinarily complex and dynamic, and to think that one can treat a multitude of conditions with histone deacetylase inhibitors is not realistic, in my opinion. Vitamin D receptor activation can increase histone acetylation (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22vitamin+D%22+histone+acetyltransferase+OR+acetylation), much as sodium butyrate supposedly does (histone deacetylase inhibition leads to increases in the acetylation of histone proteins). But it's clear, in my opinion, that a lot of the effects of sodium butyrate cannot be explained in terms of histone acetylation.
Subscribe to:
Posts (Atom)