Hepatotoxicity in rat following administration of valproic acid

Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)-plus-PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA-treated rats had significantly lower levels of serum-free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA-plus-PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of beta-oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA-plus-PB could be clinically hazardous in causing hepatic injury.