Adenosine vs. Ribose vs. AICAriboside for the Restoration of Adenosine Nucleotides in the Heart Following Ischemia

In this article [Mauser et al., 1985: (http://circres.ahajournals.org/cgi/reprint/56/2/220.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3918804)], Mauser et al. (1985) show that the intraarterial infusion of adenosine produced a 90-fold increase in the rate of adenosine nucleotide resynthesis (mostly by purine salvage pathways), following cardiac ischemia in dogs, and infusions of equimolar dosages of ribose or AICAriboside produced only between 5-fold and 9-fold increases in the rate of adenosine nucleotide formation, by either the salvage or de novo pathways. Only adenosine significantly restored ATP levels, following ischemia. All of the compounds were infused intraarterially, into the left coronary arteries of the dogs.

This article shows, in my opinion, that adenosine is far superior to ribose as an approach to restoring adenosine nucleotide levels following their depletion, and the research casts doubt on the idea, as suggested by the authors of some articles, that the entries of the carbons of ribose, derived from exogenous purine nucleotides, into the nonoxidative pentose cycle and into glycolytic pathways make a substantial contribution to the purine-mediated protection of cultured cells, such as astrocytes, against death due to glucose deprivation or other conditions. In most of those articles, the only evidence that ribose mediates the protective effects is that purine nucleoside phosphorylase (PNP) inhibitors sometimes block the protective effects of exogenous purines. But, as discussed by other authors, that doesn't mean that the use of ribose as a glycolytic substrate mediates the protective effects of purines or that ribose can substitute for the preformed nucleotides. It may just mean that ribose-1-phosphate has to be derived from nucleoside phosphorolysis to maintain purine salvage and that, paradoxically, more purine nucleobases are lost when ribose is "locked" in nucleosides and nucleotides than are lost when some turnover of nucleoside-derived ribose is allowed to occur, via the PNP-mediated formation of ribose-1-phosphate and purine bases. Also, the inhibition of nucleoside phosphorolysis prevents the formation of uric acid from the exogenous purines, and some authors have suggested that uric acid-induced peroxynitrite scavenging may partially mediate the protective effects of purines on cultured cells. There's a lot of research showing that uric acid can maintain mitochondrial functioning, in cells in the liver or in other cells, by preventing the inactivation of respiratory-chain enzymes by peroxynitrite, etc. Additionally, adenosine is normally kept at a very low concentration intracellularly, and massive amounts of adenosine have to be supplied, normally, to produce adenosine-mediated toxic effects and S-adenosylhomocysteine accumulation, etc., in cells [usually 1 mM (1000 uM) or higher of extracellular adenosine is required, a concentration that is supraphysiological] [Adair, 2005: (http://ajpregu.physiology.org/cgi/content/full/289/2/R283)(http://www.ncbi.nlm.nih.gov/pubmed/16014444)]. If adenosine were to accumulate as a result of PNP inhibition, that accumulation could produce toxic effects. But adenosine is normally metabolized extremely rapidly.

The rate of de novo purine biosynthesis is extremely slow, and this is one reason, as Mauser et al. (1985) discussed, that AICAr did not produce very significant restorative effects on adenosine nucleotide levels. Ribose did not even appear to contribute much to purine salvage, in my opinion, in comparison to the effects of adenosine. Even if the effects of ribose depended on its metabolism into glycolytic intermediates, the presence of the preformed purine nucleotides, such as can be derived from exogenous adenosine, appear to be crucial and to be a limiting factor in the rate of ATP resynthesis and nucleotide replenishment following ischemia. There are other articles that provide similar data.

In the case of pyrimidines, the research showing that uridine phosphorylase (UP) inhibition can abolish the cytoprotective effects of exogenous uridine, as in astrocytes, tends to not take into account the role that UP is thought to play in the salvage of uracil in rodents and cultured astrocytes, etc. The traditional view is that pyrimidine bases are not salvaged and that pyrimidine salvage occurs only at the level of the whole nucleoside, meaning that the main salvage pathway for uridine, for example, is its phosphorylation to UMP by uridine kinase. Some of these articles discuss the fact that, in the brains of rodents, UP appears to play an "anabolic," rather than catabolic, role and to be required for pyrimidine salvage [Mascia et al., 1999, etc.: (http://scholar.google.com/scholar?q=%22uridine+phosphorylase%22+salvage&hl=en&lr=)]. Also, inhibition UP may indirectly inhibit purine salvage, given that UP inhibition would prevent uridine from serving as a source of ribose-1-phosphate. This could decrease the formation of PRPP from uridine-derived ribose-1-phosphate, thereby increasing the loss of purines and compromising both ATP formation and the ATP-dependent salvage of uridine, etc. The depletion of purines has been shown to lead to secondary depletion of pyrimidines, even in the context of the fructose-induced depletion of ATP from the liver. Fructose has been shown to transiently elevate plasma uridine levels, and that's very much a pathological effect, in my opinion. Some people seem to think that the fructose-induced elevation of plasma uric acid levels is "good" or desirable, given that uric acid scavenges peroxynitrite. But the elevations in uric acid levels, following fructose ingestion or infusion, are mainly the result of pronounced ATP depletion in the liver, in my opinion (and as shown by countless articles). That's not desirable. In any case, the articles in these areas are interesting.

Folate and UVB Papers in Pdf Format

Here are my old papers, with the diagrams included, in pdf format. I now think that reduced folates, such as L-leucovorin (L-folinic acid) and L-methylfolate, are far superior to folic acid, for many reasons, but the concepts discussed in the folic acid paper are still "valid." Here's the paper on folate metabolism in relation to purine and pyrimidine metabolism (http://www.mediafire.com/?zmfojwc4am2), and here's the paper on the effects of cutaneous UVB/UVA exposure on sensory neurons and projection neurons/wide-dynamic-range neurons in the dorsal horn and caudal trigeminal nucleus, etc. (http://www.mediafire.com/?410jmzmrjjm).

Competitive Inhibitory Effects of Vitamin B6 and Vitamin B3 on NAD+ and PLP Formation; Narrow and Variable Therapeutic Margin for Vitamin B3 (and B6)

I was remembering that vitamin B6 and vitamin B3 are very structurally similar, and researchers have found that each one is capable of inhibiting the biosynthesis of the other's coenzymes. The relevance of this is that, in my opinion, a decrease in the dosage of B6 has the potential to augment the effects of B3 and vice-versa, and this importance of the ratio of B3 to B6 is potentially significant. Niacinamide and niacin are the two most-commonly supplied forms of vitamin B3, but I'm mainly discussing the effects of niacinamide, here. Niacin has other effects on lipid metabolism that niacinamide doesn't have. I'm going to refer to niacinamide as "B3" because I'm tired of typing out the long names.

I don't feel like discussing all the potential problems with high doses of B3, but B3 can, in my opinion, produce effects that are consistent with either poly(ADP)-ribose (PAR) accumulation, resulting from the utilization of B3-derived NAD+ as a substrate for poly(ADP)-ribose polymerase and other enzymes participating in ADP-ribosylation [Hassa et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1594587)(http://www.ncbi.nlm.nih.gov/pubmed/16959969)], and the associated PRPP and ATP depletion or with increases in iNOS activity, etc. It can cause thrombocytopenia [Rottembourg et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16316377)], which could be a result of the hypophosphatemia that it's also been shown to cause [Muller et al., 2007: (http://cjasn.asnjournals.org/cgi/content/full/2/6/1249)(http://www.ncbi.nlm.nih.gov/pubmed/17913971); Takahashi et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/14871431)], and also liver dysfunction [many, many references, including probably those referring to "pruritus" from niacinamide, refer to liver dysfunction from high doses of niacinamide and niacin (cholestasis commonly causes pruritus)], either by interfering with PLP formation or depleting SAM-e in the formation of N-methylniacinamide or by increasing iNOS activity or NADPH oxidase activity, etc., etc. The thrombocytopenia appears to require rather high doses, such as 1000 mg/d (Rottembourg et al., 2005), but I wouldn't assume that any dose, above some minimal dose, is absolutely not going to cause problems. (Nicotinamide is the same thing as niacinamide.) On the other hand, B3 deficiency can cause fatty liver disease. But I generally think the effects of B3 on iNOS or PARP or NADPH oxidases can get out of control very quickly, and it's sort of like vitamin B2 and ubiquinone in that regard, in my opinion. There's much more of a rationale for using somewhat higher dosages of, for example, vitamin B5, vitamin B1, and biotin, in my opinion. But even those cofactors can lower free fatty acids excessively, as in the case of vitamin B5, or produce effects, just by their normal mechanisms, that are not always going to be desirable, in my view. But they don't really have the potential to participate in these wild, redox cycling reactions that vitamins B2 and B3 (and coenzyme Q10) can, in my opinion, participate in and facilitate.

So there's a narrow dosage range (I would define a crude, therapeutic dosage range for niacinamide as 25-75 mg/d or something, but it's possible that most of the benefits would begin to plateau at doses lower than that or at the lower end of that range), and there can be a danger in, for example, reducing the dose of B6 and finding that some aberrant or undesirable effects occur. These are all just my opinions, of course. One could erroneously conclude that the effects of a decrease in the B6 dosage are "bad" because of the B6 reduction. In reality, the "bad" effects might merely be the result of a disinhibition of the biosynthesis of NAD+ from B3, resulting from the absence of such a pronounced inhibitory effect of pyridoxine or pyridoxal or PLP on nicotinamide phosphoribosyltransferase activity, etc.

People are constantly drawing inappropriate conclusions about B3 metabolism in the literature. For example, the absence of a decrease in NAD+ levels does not necessarily mean that PAR levels have not been increased in response to exogenous B3. The B3 moiety of NAD+ can be recycled (niacinamide is the main product of the PARP reactions), but this recycling could, in my opinion, amount to a kind of ATP and PRPP depleting futile cycle. PARP contains ADP-ribose but does not sequester the actual nicotinamide (B3) moiety of NAD+, but a small increase in the pool of available, recyclable nicotinamide could conceivably waste a lot of adenine nucleotides and PRPP and ATP in the *acceleration* of ADP-ribosylation reactions. NAD+ is also a cofactor of iNOS and other NADPH oxidase enzymes, and extra B3 could just augment the formation of excessive iNOS-derived nitric oxide and produce other reactive oxygen species, in my opinion. NO (nitric oxide) also activates PARP activity, etc. People seem to think that the iNOS protein concentration and activity, in a given tissue, cannot be elevated unless a person is septic or falling on the floor from some overwhelming inflammatory disease, but this is not the case, in my view. Of course, if one thinks that NAD+ levels are going to be maximized in response to an intake of 0.5 mg per day of B3, because the National Research Council says so (I forget what it's called), then one also isn't going to be able to understand the dose-response effects of B3.

These interactions between B3 and B6 have been researched in the context of "pellagra," which is defined as a B3 deficiency disease but that can actually result from either B6 or B3 deficiencies or both. The most well-known effect is the competitive inhibition of pyridoxal kinase by niacin or niacinamide or both, and this can cause pellagra-like photosensitivity (some of the kynurenine intermediates are, apart from the porphyrins, the only known endogenously-produced photosensitizing compounds) and other effects by interfering with the B6-dependent metabolism of tryptophan. These interactions can be complex, because B6 depletion disrupts the metabolism of tryptophan to niacin (niacin can be made from tryptophan in humans, in the so-called "kynurenine pathway"). This can cause intermediates in the kynurenine pathway to accumulate, and many of these can inhibit pyridoxal kinase, the enzyme that forms PLP. That further deranges the kynurenine pathway, etc. Pyridoxal kinase is inhibited by 3-hydroxykynurenine, 3-hydroxyanthranilate, xanthurenate (i.e. xanthurenic acid), and picolinate (i.e. picolinic acid) [Takeuchi and Shibata, 1984: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1153685&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6466295)]. That article is actually good and may help explain some of the reports of adverse effects from free-form L-tryptophan, in my opinion. I've discussed that in past postings, but Takeuchi and Shibata (1984) discuss the very high Km values for the bindings of substrates to some of those kynurenine-pathway enzymes, etc. Some of the effects of "B3 pellagra" are, obviously, just caused, proximally, by NAD+ depletion. Essentially all niacinamide is thought to be initially converted into NAD+ in vivo, but niacin is metabolized differently. I forget the precise differences, but niacin causes hypolipidemic and vasodilating ("flushing") effects by increasing prostaglandin production (by some mechanisms that I forget). But the point is that in "B3 pellagra," there isn't enough quinolinic acid available for niacin and NAD+ synthesis (see Hassa et al., 2006). As a result, more tryptophan is diverted down the kynurenine pathway that converts tryptophan to quinolinic acid, and this increases the turnover of the PLP and causes those intermediates to build up and further deplete PLP (by decreasing its formation), etc. Here are a couple other articles(not great examples) that discuss some of these interactions [Darvay et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10354170); Siniscalchi et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16039138)]. Some drugs, such as theophylline in high doses, inhibit pyridoxal kinase also, etc.