Mechanism of allyl alcohol toxicity and protective effects of low-molecular-weight thiols studied with isolated rat hepatocytes.
Freshly isolated hepatocytes from male rats were incubated with allyl alcohol at concentrations up to 2 mM. Allyl alcohol exerted a dose-dependent toxicity on the cells which was inversely related to cellular glutathione (GSH) content and accordingly influenced by stimulation as well as inhibition of GSH synthesis. The toxicity was prevented by inhibitors of alcohol dehydrogenase and augmented by the aldehyde dehydrogenase inhibitor disulfiram, suggesting that the toxic metabolite was the reactive aldehyde acrolein. The pattern of hepatocellular metabolism of allyl alcohol was monitored by high-pressure liquid chromatography (HPLC) analysis. The results suggest that acrolein, which is formed by the activity of alcohol dehydrogenase, preferentially reacts with cellular GSH to form an aldehyde-GSH adduct which subsequently is metabolized to the corresponding acid. In addition, a thiohemiacetal may be produced and subsequently degraded. In cells depleted of GSH, acrolein may react with essential macromolecules and thereby lead to structural and functional derangement and, eventually, irreversible injury.
Ohno
Y
Y
Ormstad
K
K
Ross
D
D
Orrenius
S
S
D000433:1-Propanol / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D000171:Acrolein / Q000378:metabolism; D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020005:Propanols; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D020005:Propanols; D011720:Pyrazoles; C031280:pyrazole; C006463:allyl alcohol; D000171:Acrolein; D000433:1-Propanol; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; D004221:Disulfiram