Biological activity of racemic folate mixtures fed to folate-depleted rats

Most commercially available tretrahydro and substituted folates are racemic mixtures of R and S isomers about pteridine-carbon 6. Some reports show the unnatural stereoisomers modify specific aspects of folate metabolism, whereas others show no significantly different biologic effects between isomers. The extent to which unnatural folate stereoisomers are inert in vivo is unclear. Possible interactions between isomers at normal dietary folate intakes were tested by comparing growth, liver and serum folate concentrations, and congener patterns of folate-depleted rats fed amino acid-based diets with 283, 566 or 1132 nmol folic acid (standards), or 566 nmol racemic 5-methyltetrahydrofolate, 5-formyltetrahydrofolate or 5,10-diformyltetrahydrofolate/kg diet for 3 wk. Growth and tissue folate levels increased with each increment in dietary folic acid. Growth and liver and serum folate concentrations of rats fed 566 nmol 5-formyltetrahydrofolate or 5-methyltetrahydrofolate/kg diet were similar to those of rats fed 283 nmol folic acid/kg diet. Rats fed 5,10-diformyltetrahydrofolate lost weight and had depressed serum folate levels, and most died. Results show that biologic activity of racemic 5-formyltetrahydrofolate and 5-methyltetrahydrofolate was half that of folic acid, and the R isomer did not affect growth at the levels fed. Addition of a second formyl group destroyed folate bioactivity. The folate-depleted rat model is useful for testing biologic effects of individual folate stereoisomers in vivo as they become commercially available.