Early Structural and Functional Changes in Liver of Rats Treated with a Single Dose of Valproic Acid

Abstract

Valproic acid (VPA) is a simple fatty acid largely used as anticonvulsivant agent. Side effects are uncommon, but cases of fatal hepatic failure have been reported. To elucidate the mechanism of VPA‐induced hepatotoxicity, the functional and structural changes associated with administration of sodium valproate (NaVPA) to rats (200 or 600 mg per kg, i.p.) were analyzed. NaVPA produced an immediate, dose‐dependent and prolonged increase in bile salt‐independent bile flow with a decrease in biliary cholesterol and phospholipid output. At 3 and 5 hr, marked ultrastruc‐tural changes were evident in hepatocytes, including formation of autophagic vacuoles engulfing altered mitochondria and occasionally peroxisomes. A modest accumulation of lipoprotein particles was evident at 5 hr in the Golgi cisternae. Twelve‐hour samples appeared normal. Bile canaliculi and junctional complexes remained unaltered throughout. The changes observed differ from those previously reported with other hydrocholeretics, such as diethylmaleate; they are likely related to hepatic biotransformation of VPA, which undergoes β and ω‐oxidation, and glucuronidation. While VPA‐induced choleresis reflects the physiological osmotic effect of the glucuronide excreted in bile, the ultrastructural changes likely reflect interference by VPA with β‐oxidation of endogenous fatty acids and temporary accumulation of transformation products in the mitochondrial matrix.