The role of aldehyde oxidase in ethanol-induced hepatic lipid peroxidation in the rat.
Hepatic lipid peroxidation has been implicated in the pathogenesis of alcohol-induced liver injury, but the mechanism(s) by which ethanol metabolism or resultant free radicals initiate lipid peroxidation is not fully defined. The role of the molybdenum-containing enzymes aldehyde oxidase and xanthine oxidase in the generation of such free radicals was investigated by measuring alkane production (lipoperoxidation products) in isolated rat hepatocytes during ethanol metabolism. Inhibition of aldehyde oxidase and xanthine oxidase (by feeding tungstate at 100 mg/day per kg) decreased alkane production (80-95%), whereas allopurinol (20 mg/kg by mouth), a marked inhibitor of xanthine oxidase, inhibited alkane production by only 35-50%. Addition of acetaldehyde (0-100 microM) (in the presence of 50 microM-4-methylpyrazole) increased alkane production in a dose-dependent manner (Km of aldehyde oxidase for acetaldehyde 1 mM); menadione, an inhibitor of aldehyde oxidase, virtually inhibited alkane production. Desferrioxamine (5-10 microM) completely abolished alkane production induced by both ethanol and acetaldehyde, indicating the importance of catalytic iron. Thus free radicals generated during the metabolism of acetaldehyde by aldehyde oxidase may be a fundamental mechanism in the initiation of alcohol-induced liver injury.
Shaw
S
S
Department of Medicine, V.A. Medical Center, Bronx, NY 10468.
Jayatilleke
E
E
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology* / Q000633:toxicity; D006519:Hepatitis, Alcoholic / Q000201:enzymology / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014414:Tungsten / Q000494:pharmacology; D014812:Vitamin K / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D014812:Vitamin K; D000431:Ethanol; D000493:Allopurinol; D014969:Xanthine Oxidase; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D003676:Deferoxamine; D014414:Tungsten