This article [Hartwig, 2001: (http://www.curesnaturally.com/Articles/Science/3MgMutagenesis.pdf)
(http://www.ncbi.nlm.nih.gov/pubmed/11295157)] is interesting, and the author discusses research showing that depletion of intracellular magnesium may, by a variety of mechanisms, increase the likelihood that DNA damage will occur in the cell. Hartwig (2001) discusses the fact that magnesium binds to DNA polymerase enzymes and is evidently serves a "preferred" role as a cofactor or regulatory cation in that regard. I'm not clear on what the mechanism is, because it sounds as if magnesium is just complexed with the phosphate groups of the nucleotide triphosphates that are serving as substrates for the DNA polymerases. I guess that's not the case, but the article doesn't explain the mechanism in a way that's especially clear. Magnesium or one of a variety of transition metals, such as manganese or nickel, can evidently stabilize the transition states of the polymerization reactions catalyzed by the polymerase enzymes, but the substitute cations (the transition metals) are poor substitutes and lead to increases in errors, thereby potentially resulting in damage, during DNA replication. The intracellular magnesium content can also affect the activities of DNA excision repair enzymes, as the author discusses.
That's a really original and interesting article, even if the mechanisms underlying those effects of magnesium are still not especially clear. I think there is something to it, though, and the physiological and pharmacological effects of magnesium are really complicated. The articles that have cited that article by Hartwig (2001) probably go into some of the mechanisms, but I don't feel like looking through them right now [(http://scholar.google.com/scholar?num=50&hl=en&lr=&safe=off&cites=15766567627687007705)]. Dietary vitamin D can increase magnesium absorption [Miller et al., 1965: (http://jn.nutrition.org/cgi/reprint/85/3/255.pdf); Hardwick et al., 1991: (http://jn.nutrition.org/cgi/reprint/121/1/13.pdf) (http://www.ncbi.nlm.nih.gov/pubmed/1992050)], but there's some evidence that an increase in vitamin D intake may simultaneously increases the urinary excretion of magnesium (Hardwick et al., 1991). Nonetheless, Montgomery et al. (2004) [Montgomery et al., 2004: (http://www.animal-science.org/cgi/content/full/82/9/2742) (http://www.ncbi.nlm.nih.gov/pubmed/15452920?dopt=Abstract)] found that supplemental vitamin D3 did increase the intracellular phosphorus, magnesium, and calcium concentrations, expressed on a per-mg-cellular-protein basis, in the muscles of steers, and Miller et al. (1965), cited above, did find that an adequate vitamin D intake produced a net increase in magnesium retention. There are other articles that show graded increases in magnesium absorption with increasing serum 25-hydroxyvitamin D [25(OH)D] levels, but I don't feel like finding them now.
The capacity of an adequate vitamin D intake to prevent urinary phosphate loss might also be an important factor that could interact with the effects of magnesium on carbohydrate metabolism and nucleotide metabolism. Weisinger and Bellorin-Font (1998) [Weisinger and Bellorin-Font, 1998: (http://ca.geocities.com/mim_nephro/LancetMgP.pdf)
(http://www.ncbi.nlm.nih.gov/pubmed/9717944)] discuss research showing that an adequate supply of vitamin D helps to prevent hypophosphatemia by decreasing parathyroid hormone (PTH) levels. Kalaitzidis et al. (2005) found that low levels of serum phosphate and magnesium were associated with insulin resistance and other features of the so-called "metabolic syndrome" [Kalaitzidis et al., 2005: (http://www.nephrology.uoi.gr/uliko/Dimosievseis_engl_pdf/176.pdf)
(http://www.ncbi.nlm.nih.gov/pubmed/15861350)]. The authors discuss the fact that phosphate availability is important in carbohydrate metabolism, and magnesium obviously has many effects on carbohydrate metabolism.
The fact that an adequate supply of vitamin D can both lower serum PTH levels and increase or maintain intracellular phosphate concentrations is very significant, in my opinion, in part because of the "fragile" qualities of phosphate homeostasis. Supplementing with phosphate tends to be very problematic, unless there is some specific cause, such as renal failure, that makes supplementation, under a doctor's supervision, a valid approach. An increase in phosphate intake tends to reliably increase PTH levels, and the increased levels of PTH simply increase urinary phosphate excretion and can exacerbate acid-base abnormalities. For example, Ambuhl et al. (1999), cited below, found that serum bicarbonate levels increased progressively in response to phosphate supplementation. That would be an undesirable effect, in my opinion, for numerous reasons. Although Ambuhl et al. (1999) did not find a significant decrease in serum calcium in response to phosphate supplementation, other researchers have found that increases in phosphate intake can decrease serum calcium. In past postings [(http://hardcorephysiologyfun.blogspot.com/2009/02/potential-for-hypophosphatemia-or.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html)], I've suggested that one approach might be to obtain a reasonable amount of calcium from foods (i.e. a total intake of 500-1000 mg/d or something or to just not get enormous amounts of calcium from foods, as so many people are advocating these days), to not supplement with calcium, and to supplement with vitamin D and magnesium. That's just my opinion, and one should obviously talk about that with his or her doctor. Apart from the potential for calcium-induced hypercoagulability at high dietary intake ratios of Ca2+/Mg2+ (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html), Lau et al. (1984) [Lau et al., 1984: (http://www.ncbi.nlm.nih.gov/pubmed/6703070)] found that a high dietary intake of calcium strongly reduced phosphate absorption, decreased serum phosphate, and increased magnesium excretion in the urine to a pathological degree. The binding of calcium and phosphate in the G.I. tract is well-known. Given that both calcium and vitamin D decrease serum PTH levels and increase serum calcium levels slightly (and given that higher vitamin D intakes would be expected to increase or maintain serum or tissue phosphate and magnesium levels, while high dietary calcium intakes could be expected to decrease serum phosphate and magnesium levels), an increase in dietary vitamin D to an adequate level seems to me to be a better approach, in comparison to these excessive increases in dietary calcium, to decreasing serum PTH levels and maintaining serum calcium levels in the long term. There's considerable evidence that an increase in dietary vitamin D decreases serum PTH, in part or even largely, by leading to an increase in the localized production of hormonal vitamin D, 1alpha,25-dihydroxyvitamin D, from 25-hydroxyvitamin D in the parathyroid gland [Vieth et al., 2003: (http://jcem.endojournals.org/cgi/content/full/88/1/185) (http://www.ncbi.nlm.nih.gov/pubmed/12519850?dopt=Abstract)]. Magnesium deficiency is thought to produce resistance to the various signals that regulate PTH output by the parathyroid gland, in part by reducing adenylate cyclase activity in the parathyroid gland (Weisinger and Bellorin-Font, 1998). But that's unlikely to be a mechanism mediating the PTH-suppressing effects of increases in vitamin D intake, in my opinion. The main message of the article by Vieth et al. (2003) is that, past a certain level of 25-hydroxyvitamin D, the levels of serum hormonal vitamin D [1alpha,25(OH)2D] will plateau or actually decrease. As the 25(OH)D levels increase more, the suppression of PTH levels will continue to increase, as a result of the autocrine or paracrine conversion of 25(OH)D into hormonal vitamin D in the parathyroid glands. That capacity of vitamin D to decrease PTH levels without also decreasing serum phosphate levels is very unusual and important, in my opinion, and it's not an effect that can be reproduced by taking massive amounts of calcium, in my opinion.
As long as one recognizes that this article [Ambuhl et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10561144)] is not meant to suggest that phosphate supplementation in normal people is a good idea, the results are very important, in my opinion. Ambuhl et al. (1999) found that restoring normal phosphate levels in people with renal failure increased the concentrations of ATP and other high-energy phosphate compounds in the muscles of the people whose phosphate homeostasis had been normalized. The really interesting thing is the discussion by the authors of the way in which the tissue phosphate levels tend to not correlate very reliably with the serum phosphate levels. Hypophosphatemia and hyperphosphatemia are both very dangerous, and the authors were not really saying that serum phosphate measurements are invalid or unimportant. But the authors were saying that, within the normal range of serum phosphate values, the tissue phosphate concentrations can vary considerably. In support of that concept, Ambuhl et al. (1999) found that the mean serum phosphate levels were within the normal range in both the control group and the phosphate-supplemented group by the end of the study period.
The point of that article is that the prevention of excessive urinary phosphate excretion and maintenance of serum phosphate levels can have significant effects. The association of normal or higher serum phosphate levels with higher insulin sensitivity is really important, in my opinion. Although the correction of severe magnesium deficiency can increase serum PTH and serum calcium levels initially, this is not a graded phenomenon and represents a restoration of the normal homeostatic regulatory mechanisms (Weisinger and Bellorin-Font, 1998). I mention that because it's mentioned frequently in the literature and isn't always put in the proper context.
No comments:
Post a Comment