The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies.

Valproic acid (VPA), its unsaturated metabolites and pent-4-enoate (4-PA) were studied for potential hepatotoxicity in rats. 4-PA, 4-en-VPA and 2,4-dien-VPA were potent inducers of microvesicular steatosis in young rats. Microvesicular steatosis induced by the 4-en-VPA was accompanied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormalities. Myeloid bodies and lipid vacuoles were seen to a lesser extent in 2,4-dien-VPA and 4-PA-treated rats. VPA failed to induce discernible liver lesions in young rats even at near lethal doses of 700 mg per kg per day. The drug did, however, induce hepatic lipid accumulation in mature rats and in young rats dosed concomitantly with phenobarbital. beta-oxidation inhibition and several other biochemical alterations were observed in rats dosed with VPA, its unsaturated metabolites and 4-PA. It was suggested that beta-oxidation inhibition observed in both VPA and en-metabolite-treated rats occurred by different mechanisms. VPA inhibits by a transient sequestering of CoA while the CoA esters of some en-VPA-metabolites, particularly 4-en-VPA, inhibit specific enzyme(s) in the beta-oxidation sequences.