Effect of chronic valproate treatment on folate-dependent methyl biosynthesis in the rat

Folate deficiency has been associated with chronic anticonvulsant therapy. Characterization of the effects of individual anticonvulsants has been undertaken. Chronic treatment of rats with sodium valproate caused a decrease in liver folate concentration with concomitant increases in brain and plasma folate concentrations. After several weeks, these trends were reversed and folate concentrations tended to normalize. Chronic valproate treatment affected the activities of folate-dependent one-carbon enzymes: Serine hydroxymethyltransferase activity in liver was increased; methylenetetrahydrofolate reductase activity in both brain and liver was decreased; and methyltetrahydrofolate:homocysteine methyltransferase activity in both brain and liver decreased initially but returned toward normal with continued treatment. Methionine adenosyltransferase activity in brain declined after several weeks of treatment but the concentration of S-adenosylmethionine in liver increased with chronic valproate treatment. These data are consistent with the hypothesis that the effects of anticonvulsants on folates are a consequence of the mechanism of action of the anticonvulsant.