Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity

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 thera peutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistan t than controls, as evidenced by a significant cytotoxic response after cha llenge 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 addi tive effect. Incubation with valproic acid plus allyl alcohol induced an ir reversible depletion of hepatocellular glutathione, in contrast to allyl al cohol alone which induced a transient loss. Hepatocytes treated with valpro ic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatoce llular 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.