Lipid peroxidation as a mechanism of alcoholic liver injury: role of iron mobilization and microsomal induction.
Lipid peroxidation has been invoked as a mechanism of alcoholic liver injury but its role has been controversial and the mechanism by which it occurs is unclear. Catalytic iron is known to play an important role in cellular injury and is produced during mobilization of ferritin iron. In vivo administration of a large acute dose of ethanol (5 g/kg) which produces hepatic lipid peroxidation in chow-fed rats resulted in mobilization of non-heme iron. The generation of NADH from alcohol metabolism via ADH or superoxide from acetaldehyde-xanthine oxidase mobilized iron from horse spleen ferritin in vitro. Chronic feeding of alcohol as 36% of energy for 6 weeks does not itself produce peroxidation in the rat but potentiates acute effects of ethanol. It produced microsomal induction which enhanced iron-stimulated lipid peroxidation and increased hepatic non-heme iron. Carbon monoxide increased rather than decreased accumulation of microsomal peroxidation products in vitro suggesting that cytochrome P-450 reductase mediates peroxidation but cytochrome P-450 may metabolize products. Incubation at lowered oxygen tensions equivalent to those observed in the perivenular zone (pO2 = 24 mmHg) enhanced in vitro iron mobilization but decreased peroxidation. Lipid peroxidation and its stimulation by iron mobilization and microsomal induction may be an important contributory mechanism of alcohol-induced liver injury.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D000431:Ethanol; D005293:Ferritins; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D009251:NADPH-Ferrihemoprotein Reductase; D009245:NADH Dehydrogenase