Effects of Folinic Acid vs. Folic Acid on Purine Metabolism; Relationship to the Cytoplasmic NADPH/NADP+ ratio

Here's the article that shows folinic acid--but not folic acid--decreases the methotrexate-induced increases in urinary AICA [AICA is the dephosphorylated nucleoside of AICAriboside (AICAr), and AICAr is the de-ribosylated "base" of AICAribotide, a.k.a ZMP]. I'm remembering what a great article this is, and it also shows that low-dose methotrexate rapidly decreases plasma hypoxanthine and uric acid in vivo. That shows the magnitude of the effects of antifolates on purine metabolism:

http://www3.interscience.wiley.com/cgi-bin/fulltext/109677274/PDFSTART
(pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/15476202)

The authors talk about the usual mechanistic explanation for the lack of effectiveness of folic acid, and the explanation is that methotrexate-derived polyglutamates inhibit dihydrofolate reductase and thereby prevent folic acid from being converted into 10-formyltetrahydrofolate, the cofactor of AICAR transformylase (the normally-"rate-limiting" step in de novo purine formation). That explanation is valid, but I think the larger point is that the reduced folates, as a group, would be expected to bypass any deficits in the cytoplasmic redox state that would tend to decrease, for example, the NADPH/NADP+ ratio. The conversion of folic acid into THF requires four sequential cycles ("turnover cycles") of dihydrofolate reductase, and this requires NADPH. Methylenetetrahydrofolate reductase also requires NADPH, and its activity would be expected to depend on the cytoplasmic NADPH/NADP+ ratio. This article illustrates the concept in the case of the metabolism of methotrexate intracellularly, but the same concept could be helpful for understanding the potential advantages of using reduced folates, including 5-methyltetrahydrofolate (methylfolate), to enhance purine salvage in the brain, etc.:

http://cancerres.aacrjournals.org/cgi/content/abstract/44/6/2325
(pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/6609765?dopt=Abstract)

That's an interesting article, and, for some reason, the influence of the cytoplasmic redox state (NADPH/NADP+ ratio) on DHF reductase and methylenetetrahydrofolate reductase has never really been addressed in the literature. The same concept would apply to the mitochondrial enzymes that utilize folate-derived cofactors, and the preferred, intramitochondrial directionality of those enzymes' activities can be explained in terms of the mitochondrial NAD+/NADH ratio. The redox state would be dependent on mitochondrial functioning, and mitochondrial deficits (which are not uncommon in many disease states) could seriously disrupt one-carbon metabolism.

I know there are some articles showing the more pronounced effects, in comparison to folic acid, of reduced folates on purine metabolism, and I'll try to go through some of them that I have.