Acute valproate administration impairs methionine metabolism in rats

Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug.