Great Article on the Pharmacological Aspects of Different Folates

This is a really great article on the pharmacokinetics of folic acid in relation to methylfolate, and the things the authors discuss are really good for me to learn and know:

http://www3.interscience.wiley.com/journal/118671262/abstract

It's one of the most insightful articles I've ever seen on folic acid, in some ways. One of the important things the authors mention, aside from their finding that the cells in the intestinal tract have a limited capacity to reduce and methylate folic acid [meaning that much of a dose of folic acid will enter the portal vein, liver, and circulation as folic acid and not 5-methyltetrahydrofolate (5-MTHF)], is that, especially for serum folate levels of 50 nM or higher (in a person who has taken only folic acid and not methylfolate), a significant percentage of that serum folate will be folic acid and not 5-MTHF. The commonly-used assay doesn't discriminate between 5-MTHF and folic acid, and the assumption in most of the articles is that serum folate is predominantly 5-MTHF. This apparently isn't the case. I'd been wondering about that, before I read it. I'd seen some articles talking about small increments in serum "unmetabolized" folic acid being of potential concern, in relation to T-cell proliferation, I think. I don't think it would be a concern at reasonable intakes of folic acid, but it could be at higher ones (the authors of that article I link to note that folic acid could accumulate intracellularly in the cells of extrahepatic tissues and disrupt the folate cycle).

The more important implication is that, at any given level of serum folate, one cannot tell what the impact, the benefit or even harm, of that serum folate value would be for extrahepatic cells (or for cells in the liver, for that matter). The liver would probably be the organ in which the accumulation of unmetabolized folic acid would become a dose-limiting concern, for a person taking folic acid (but not as much methylfolate). The lack of discrimination by the serum folate assay is a major issue for interpreting articles about serum folate correlations with diseases, etc. It's mainly because the folate receptor, the transporter that preferentially transports folic acid into cells, has a much lower capacity for transport than the reduced folate carrier, I think. I forget the details, but I'll have to read on that.