Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Abstract

Abstract:The influence of the antiepileptic drug, valproic acid (2‐n‐propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25–1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non‐toxic dose of allyl alcohol (2‐propen‐1‐ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N‐acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.