Mechanism of decrease in serum folate levels of rats receiving diphenylhydantoin.

Decreased serum folate levels of patients receiving anticonvulsants have been well documented (Klipstein 1964; Reynolds 1968; Dahlke and Mertens-Roeslei 1967; Horwitz et al. 1968; Jensen and Olesen 1969; Houben et al. 1971). At present time, however, the mechanism for this abnormality seems to be remaining unsolved, even though several attractive theories have been advanced, that is, an increased requirement for tetrahydrofolate by hepatic microsomal hydroxylating enzymes which are induced by diphenylhydantoin administration (Andreasen et al. 1971; Kudd et al. 1964; Maxwell et al. 1972; Raylis et al. 1971), and an interference with folic acid absorption due to inhibition of intestinal conjugase by diphenylhydantoin administration with conflicting conclusions (Hoff brand and Necheles 1968; Rosenberg et al. 1968; Baugh and Krumdieck 1969; Bernstein et al. 1970; Perry and Chanarin 1972). Results of present investigations of ours using growing rats revealed that 1, a decrease in serum folate levels of rats receiving diphenylhydantoin was partly due to a reflexion of a decreased level of N5-methyltetrahydrofolate in the liver of these rats, 2) the decreased level of N5-methyltetrahydrofolate was resulted from an elevation of N5-methyltetrahydrofolate-homocysteine transmethylase activity, and 3) the elevation of the enzyme activity was resulted from a) an increased production of the N5-methyltetrahydrofolate-homocysteine-transmethylase apoenzyme by