Allyl alcohol- and acrolein-induced toxicity in isolated rat hepatocytes.
Incubation of isolated hepatocytes with allyl alcohol results in GSH depletion and subsequent cytotoxicity which is prevented by pyrazole, an inhibitor of alcohol dehydrogenase. Both GSH depletion and cytotoxicity were much more rapid when hepatocytes were incubated with acrolein, the reactive metabolite, and were not affected by pyrazole. However, cytotoxicity of both allyl alcohol and acrolein was enhanced by the aldehyde dehydrogenase inhibitors cyanamide and disulfiram. Malondialdehyde, a lipid peroxidation product, was also formed when hepatocytes were incubated with either agent, and treatment of the hepatocytes with a ferric ion chelator, desferrioxamine, or an antioxidant delayed the cytotoxicity without affecting GSH depletion. Although no GSSG was formed and addition of disulfide reductant dithiothreitol did not restore GSH levels, cytotoxicity was prevented if dithiothreitol was added some time after either agent.
Silva
J M
JM
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
O'Brien
P J
PJ
D000433:1-Propanol / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003484:Cyanamide / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020005:Propanols; D051381:Rats; D011919:Rats, Inbred Strains
D000447:Aldehydes; D020005:Propanols; C006463:allyl alcohol; D003484:Cyanamide; D000171:Acrolein; D000433:1-Propanol; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; D004976:Ethacrynic Acid; D004229:Dithiothreitol; D004221:Disulfiram