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 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.
Klee
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S
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Germany. klee@rz.uni-leipzig.de
Johanssen
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S
Ungemach
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FR
D000111:Acetylcysteine / Q000627:therapeutic use*; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002478:Cells, Cultured; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D020005:Propanols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*
D000927:Anticonvulsants; D016166:Free Radical Scavengers; D020005:Propanols; C006463:allyl alcohol; D014635:Valproic Acid; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; D000111:Acetylcysteine