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.
Valproic acid (VPA) has been in clinical use in the United States since 1978. During that time, it has been incriminated as the cause of a number of instances of severe hepatic injury, some fatal (1-9). A component of the lesion, microvesicular steatosis, resembles the lesion of Reye's syndrome (10) and that of Jamaican vomiting sickness (11). Furthermore, a metabolite of VPA structurally resembles 4-pentenoic acid and hypoglycin A (4, 12) (Figure 1). 4-Pentenoic acid can produce a lesion which resembles Reye's syndrome and Jamaican vomiting sickness in experimental animals (13), and hypoglycin A is the putative agent responsible for Jamaican vomiting sickness (11). Since 4-pentenoic acid and hypoglycin A can produce microvesicular steatosis in the rat and since the metabolism of VPA in rats appears to be similar to that in man ( 14), the effort to produce the lesion with VPA seemed warranted.
Methods
Subject animals were Sprague-Dawley rats. Seventytwo mature male rats, weighing 250 to 300 gm were used in experiments 1-3. Experiment 4 involved 25 young male animals (25 to 40 days old) weighing 150 to 170 gm. Experiment 5 involved twenty-five 21-day old weanlings of both sexes with an average weight of 80 gm. VPA (Depakene") for injection was supplied by Abbott Laboratories (Chicago, Ill.).