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.
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