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.
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