Oxidative cell injury in the killing of cultured hepatocytes by allyl alcohol.
The killing of cultured hepatocytes by allyl alcohol depended on the metabolism of this hepatotoxin by alcohol dehydrogenase to the reactive electrophile, acrolein. An inhibitor of alcohol dehydrogenase, pyrazole, prevented both the toxicity of allyl alcohol and the rapid depletion of GSH. Treatment of the hepatocytes with a ferric iron chelator, deferoxamine, or an antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), prevented the cell killing but not the metabolism of allyl alcohol and the resulting depletion of GSH. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) sensitized the hepatocytes to allyl alcohol, an effect that was not attributable to the reduction in GSH with BCNU. The cell killing with allyl alcohol was preceded by the peroxidation of cellular lipids as evidence by an accumulation of malondialdehyde in the cultures. Deferoxamine and DPPD prevented the lipid peroxidation in parallel with their protection from the cell killing. These data indicate that acrolein produces an abrupt depletion of GSH that is followed by lipid peroxidation and cell death. Such oxidative cell injury is suggested to result from the inability to detoxify endogenous hydrogen peroxide and the ensuing iron-dependent formation of a potent oxidizing species. Oxidative cell injury more consistently accounts for the hepatotoxicity of allyl alcohol than does the covalent binding of acrolein to cellular macromolecules.
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
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Miccadei
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Nakae
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Kyle
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Gilfor
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Farber
D000433:1-Propanol / Q000633:toxicity; D000171:Acrolein / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D008054:Lipid Peroxides / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology; D020005:Propanols; D051381:Rats; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D010655:Phenylenediamines; D020005:Propanols; C006463:allyl alcohol; D000171:Acrolein; D000433:1-Propanol; C004845:N,N'-diphenyl-4-phenylenediamine; D005982:Glutathione Transferase; D005978:Glutathione; D003676:Deferoxamine