Open AccessEvidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity
Author(s) -
Klee Sabine,
Johanssen Sandra,
Ungemach Fritz Rupert
Publication year - 2000
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1034/j.1600-0773.2000.pto870208.x
Subject(s) - valproic acid , glutathione , oxidative stress , chemistry , pharmacology , alcohol , toxicity , hepatocyte , biochemistry , in vitro , medicine , enzyme , epilepsy , organic chemistry , psychiatry
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.