||Role of Glutathione Depletion in the Cytotoxicity of Acetaminophen in a Primary Culture System of Rat Hepatocytes.
Mitchell, D. B. ;
Acosta, D. ;
Bruckner, J. V. ;
||Procter and Gamble Co., Cincinnati, OH. Miami Valley Labs. ;Texas Univ. at Austin. Dept. of Pharmacology and Toxicology. ;Georgia Univ., Athens. Dept. of Pharmacology and Toxicology.;Health Effects Research Lab., Research Triangle Park, NC.
Laboratory animals ;
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A primary culture system of postnatal rat hepatocytes was utilized to study the cytotoxicity of acetaminophen and the toxicological significance of glutathione (GSH) depletion. The relative time of onset and magnitude of GSH depletion, lipid peroxidation and cytotoxicity were contrasted in order to gain insight into their interrelationships. Exposure of the hepatocytes to acetaminophen resulted in time-and dose-dependent depletion of cellular GSH. The acetaminophen-induced GSH depletion and ensuing lactate dehydrogenase (LDH) leakage were quite modest and delayed in onset, in contrast to that caused by iodoacetamide (IAA) and by diethylmaleate (DEM), 2 well-known depletors of GSH. There was comparable LDH leakage, irrespective of drug treatment, when GSH levels decreased to about 20% of normal. Reduction of GSH levels below the 20% threshold by IAA treatment resulted in marked LDH leakage and loss of viability.