Valproate-induced hepatic steatogenesis in rats.

The administration of high-dose valproic acid (VPA) (750 mg per kg) consistently produced significant microvesicular steatosis in mature Sprague-Dawley rats after 48 hr. Similar changes occurred in animals pretreated with phenobarbital which received a lower dose of VPA (350 mg per kg), but no steatosis was seen in animals treated with the low-dose VPA alone. The steatogenic effect of VPA is most likely mediated by a toxic metabolite. It can also be speculated that phenobarbital, by enhancing the inducing effects of the hepatic mixed-function oxidase system, may lead to increased conversion of VPA to a toxic metabolite. Young and weanling rats appeared to be resistant to the steatogenic effects of VPA. Reproduction of microvesicular steatosis in this experimental; model may permit exploration of factors that enhance or inhibit VPA-induced hepatic injury.