This article [Dierkes et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10337865)] is really interesting and shows that vitamin B12 (cobalamin) supplementation can lower serum folate levels. The mean serum folate level in this group was extremely low (9.4 nM) before the intravenous cobalamin (at 1,000 ug/week) had begun, but the cobalamin lowered the serum folate to a mean of 4.5 nM (a 47 percent reduction). The mean red blood cell (RBC) folate concentration (which is the concentration of intracellular total folates in RBC's) increased, however, from 875 to 1,013 nM, and the total homocysteine and methylmalonic acid levels decreased.
There aren't very many articles that show this type of effect, but I really think there's something to the idea that high-dose vitamin B12 by itself, without the use of reduced folates, in particular, can reduce serum folate levels or change folate metabolism in other ways that are not necessarily desirable. This article [Frater-Schroder et al., 1981: (http://www.springerlink.com/content/p5628601hv166950/)] shows that high-dose hydroxocobalamin, by itself, did not replenish the intracellular folate levels in a person with transcobalamin II deficiency. The person began to get infections and display abnormalities in her circulating granulocytes, suggestive of folate deficiency. She required folinic acid, at least temporarily, to replenish the intracellular folate levels. The article by Dierkes et al. (1999) shows that cobalamin can increase intracellular folate retention, in red blood cells or other cell types, by increasing the proportion of polyglutamylated folates (http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b12-polyglutamylation-and.html), but these increases may come at the expense of the serum folate pool. This could conceivably worsen neurological symptoms in someone with cerebral folate deficiency, for example. There are lots of anecdotal reports on the internet and elsewhere of people who take methylcobalamin in high doses and have strange side effects or experience some worsening of some symptom or another. It's easy to suggest that the dosages the people were taking were too high or to attribute their experiences to idiosyncratic reactions, but some of these mechanisms I've discussed could account for those types of effects. Methylcobalamin has been used by itself, in many trials, to treat sleep disorders, and I just don't think it's likely to be as effective, for that purpose, when a reduced folate, such as methylfolate or L-leucovorin or even racemic leucovorin, is not used in conjunction with methylcobalamin.
Another mechanism that could explain these cobalamin-induced increases in folate turnover (or changes in folate metabolism that, in the absence of exogenous folates, may be problematic) is the effect that methylmalonic acid can have on the glycine cleavage system. Hyndman et al. (2003) [Hyndman et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12601627)] found that plasma methylmalonic acid levels were positively correlated with plasma glycine levels, and the authors suggested that the known inhibition of the glycine cleavage system by methylmalonic acid, in the context of cobalamin deficiency, might be physiologically relevant. I think this is true, and I think propionyl-CoA also inhibits different steps in the glycine cleavage system. I forget which steps are inhibited, but the glycine cleavage system is only present in the liver, as far as I know. It's a multienzyme complex, and different components of the glycine cleavage system use either pyridoxine-derived PLP, as a cofactor, or tetrahydrofolate as a cofactor. The overall activities of the different enzymes convert glycine and THF to serine and 5,10-methylenetetrahydrofolate. I can't go into all the ways in which the activities of the mitochondrial and cytosolic serine hydroxymethyltransferases (cSHMT and mtSHMT) and of glycine N-methyltransferase (GNMT) interact with the glycine cleavage system, but the interactions are really interesting and complex. Deficiencies of folate, B12, or pyridoxine (vitamin B6) all elevate serum glycine in animals, and the reasons for this are not well understood. The elevations in glycine in folate deficiency in rats are really dramatic, and the authors of one article found that the reduction in serum glycine, in response to folate supplementation, was not due to increases in GNMT activity or in the activity of the glycine cleavage system. It's probably due to changes in the directionality and activity of the cSHMT and mtSHMT activities. It's too complicated to go into now, but the mtSHMT activity really needs to proceed in the serine to glycine direction normally, even though it can reverse. cSHMT activity can change directions flexibly, but exogenous glycine has been shown to seriously disturb the folate cycle in many articles. The cofactors, like cobalamin, folates, and pyridoxine, increase glycine utilization, essentially, but, at the same time, exogenous glycine can sometimes compensate for some of the effects of severe folate deficiencies. It's really complex, but changes in glycine metabolism, occurring as a result of elevated methylmalonic acid levels in cobalamin deficiency, are probably an important set of mechanisms that could explain some of the puzzling aspects of high-dose cobalamin supplementation (in the absence of concomitant supplementation with folates, particularly reduced folates). If I were to link to and discuss one or two articles on glycine metabolism, the discussion wouldn't make sense. I'd have to link to 20 articles, and it gets to be a bit much. It's interesting, though, because the articles discuss the way there's a large metabolic demand for glycine, and it's used for the biosyntheses of heme, glutathione, collagen, purines, etc. But excessive, exogenous glycine can really disturb one carbon metabolism and glycine metabolism, paradoxically.
The inhibitory effect that methylmalonic acid (and probably propionyl-CoA or other intermediates that accumulate in cobalamin deficiency) can have on the glycine cleavage system might actually help to lend credence to one of the old hypotheses about cobalamin deficiency, the "formate starvation" hypothesis. Inhibition of the glycine cleavage system could conceivably, by intervening steps or relatively directly (by reducing serine availability intramitochondrially), prevent the mtSHMT activity from proceeding in its "preferred direction" of serine-to-glycine, thereby reducing the mitochondrial export of formate and producing "formate starvation." At least that would be one explanation. Because the mtSHMT enzyme really does need to proceed in the serine-to-glycine direction, but the glycine cleavage system, either always or most of the time, proceeds in the glycine-to-serine direction (providing serine from the oxidative metabolism of glycine). There's one article talking about an intramitochondrial "methylene trap" (5,10-methylenetetrahydrofolate trap) in the context of 5,10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase deficiency (lacking all three steps in the mitochondrial, trifunctional DCS enzyme comples) in mice [Patel et al., 2003: (http://www.jbc.org/cgi/content/full/278/21/19436) (http://www.ncbi.nlm.nih.gov/pubmed/12646567?dopt=Abstract)]. That's actually relevant to the formate starvation hypothesis, given that the net result is similar, as I understand it. The cytosolic folate enzymes, as Patel et al. (2003) describe, cannot provide enough formate for purine biosynthesis, because the mtSHMT activity, in conjunction with the DCS complex, normally proceeds in a direction that produces formate intramitochondrially and exports it to the cytosol (thereby providing enough formate for purine biosynthesis). That's been shown to be the case in many other articles. Mitochondrially-derived formate is really necessary for cytosolic purine biosynthesis, particularly in proliferating cells that have high rates of activity in the de novo purine biosynthetic pathway.
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