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Jaeschke H, Kleinwaechter C, Wendel A: The role of acrolein in allyl alcohol-induced lipid peroxidation and liver cell damage in mice. Biochem Pharmacol. 1987 Jan 1;36(1):51-7.
Male NMRI mice were fed a sucrose diet for 48 hr in order to reduce the hepatic glutathione content and to level off its diurnal variation. After administration of allyl alcohol (AA: 1.1 mmol/kg), hepatic glutathione (24.3 +/- 7.0 nmol GSH/mg protein) was almost totally lost within the first 15 min (less than 0.5 nmol GSH/mg protein). Subsequently, a massive lipid peroxidation was observed, i.e. the animals exhaled 414 +/- 186 nmol ethane/kg/hr compared to 0.9 +/- 0.8 of controls, and the hepatic TBA-reactive compounds had increased from 55 +/- 16 pmol/mg protein in controls to 317 +/- 163 after 1 hr. Concomitantly, a 40-45% loss of the polyunsaturated fatty acids (arachidonic and docosahexaenoic acid) in the liver lipids was observed. About 80% of the cytosolic alcohol dehydrogenase activity and about 50% of the microsomal P450-content were destroyed. In vivo-inhibition of alcohol dehydrogenase by pyrazole or induction of aldehyde dehydrogenase by phenobarbital abolished AA-induced liver damage as well as glutathione depletion and lipid peroxidation, while inhibition of aldehyde dehydrogenase by cyanamide made a subtoxic dose of AA (0.60 mmol/kg) highly toxic. These results strongly favour the importance of acrylic acid formation as an additional detoxification pathway. Enhanced hepatic levels of glutathione protected in vivo against the damaging effects of AA. Depletion of the liver glutathione content by phorone or diethylmaleate alone caused marginally enhanced lipid peroxidation (phorone) but not liver cell damage. Monooxygenase inhibitors (metyrapone, diethyldithiocarbamate, alpha-naphthoflavone) or an inducer (benz (a) pyrene) did not affect AA-induced toxicity. The ferric iron chelator desferoxaminemethanesulfonate prevented AA-induced lipid peroxidation and liver cell damage in vivo. In vitro, acrolein alone failed to initiate lipid peroxidation in soy bean phospholipid liposomes or in mouse liver microsomes. Thus, acrolein not only impairs the glutathione defense system but also directly destroys cellular proteins and evokes lipid peroxidation by an indirect iron-depending mechanism. |
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