The effect of chronic phenytoin treatment on tissue folate concentrations and on the activities of the methyl synthetic enzymes in the rat.

The folacin-depleting effect of phenytoin has been known clinically for many years, but a systematic investigation of this effect in animals has never been undertaken. In this study we found that chronic oral phenytoin treatment (100 mg/kg every 12 hours for 8 weeks) in rats significantly affected concentrations of folates in both liver and brain. Concentration of liver folates dropped to one-third the normal level even though concentration of plasma folates was not affected. Concentration of brain folates increased over the first 2 weeks of treatment and then declined to a level approximately three-fourths the normal concentration. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) increased as a function of the length of treatment in both brain and liver, but when phenytoin was added to the MTR assay in vitro, the activity was inhibited. No significant effects of phenytoin on the activities of serine hydroxymethyltransferase (SHMT), 5-methyltetrahydrofolate:homocysteine methyltransferase (MHMT) or methionine adenosyltransferase (MAT) were observed either in vivo or in vitro. These data are consistent with the hypothesis that phenytoin interacts with the metabolism of folates at the enzymatic level.