Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment

RE Billings

The effects of phenytoin (DPH) on folate metabolism have been studied in female Swiss Webster mice. Doses of DPH which produce steady-state plasma levels of DPH in the therapeutic range of 10-20 micrograms/ml were found to decrease plasma folate levels. In addition, the in vivo oxidation rate of [14C] formate and [2-14C] histidine to 14CO2 was increased. The increased metabolic rates were accompanied by a decrease in the hepatic activity of N5, N10-methylenetetrahydrofolate (5, 10-CH2- H4folate) reductase. N5-methyltetrahydrofolate-homocysteine transmethylase (methionine synthase); EC 2.1.1.13) activity in the liver was unchanged. The distribution of folates in the liver was determined by high-pressure liquid chromatography (HPLC) and it was found that the concentration of tetrahydrofolate (H4folate) was increased in DPH-treated mice whereas the concentration of N5- methyltetrahydrofolate was decreased. These effects were observed in mice treated with DPH for 4 days, but not in mice given a single DPH injection 24 hr previously. Decreased activity of hepatic 5, 10-CH2- H4folate reductase is postulated to account for the other effects which were observed. Decreased activity presumably results in increased tissue concentrations of 5, 10-CH2-H4folate, which is in equilibrium with its dissociation products, H4folate and formaldehyde. Increased concentrations of H4folate lead to increases in the oxidation rate of formate and histidine. These effects on folate metabolism may have important implications in the pharmacological and toxicological effects of DPH.

Volume 25, Issue 3, pp. 459-466, 05/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics

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