Role of glutathione depletion in the cytotoxicity of acetaminophen in a primary culture system of rat hepatocytes.
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. Maximal LDH leakage in response to IAA and acetaminophen preceded maximal malondialdehyde (MDA) formation, suggesting that lipid peroxidation may be a consequence of cell damage as well as GSH depletion. IAA and DEM produced a comparable, modest accumulation of MDA, yet IAA was much more cytotoxic. These findings indicate that lipid peroxidation does not play a central role in hepatocellular injury by compounds which deplete GSH, although it may contribute to degeneration of the cell. As events in the cultured postnatal hepatocytes paralleled those reported in vivo, the system can be a useful and valid model with which to study mechanisms of chemical toxicity.
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000032:analysis*; D066298:In Vitro Techniques; D007461:Iodoacetates / Q000633:toxicity; D019807:Iodoacetic Acid; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008054:Lipid Peroxides / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008298:Maleates / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D007461:Iodoacetates; D008054:Lipid Peroxides; D008298:Maleates; D000082:Acetaminophen; D007770:L-Lactate Dehydrogenase; C014476:diethyl maleate; D005978:Glutathione; D019807:Iodoacetic Acid