Microsomal generation of reactive oxygen species and their possible role in alcohol hepatotoxicity.
There is increasing interest in the possible role of reactive oxygen intermediates in the hepatotoxic actions of alcohol. A variety of mechanisms exist whereby ethanol could increase oxidative stress in the liver. This article briefly reviews two of these possible mechanisms; microsomal generation of reactive oxygen intermediates, and ability of NADH to replace NADPH in promoting microsomal production of oxygen radicals. Microsomes produce superoxide and H2O2, and in the presence of iron, yield potent oxidants which are capable of oxidizing hydroxyl radical scavengers, initiating lipid peroxidation, and causing light emission. These reactions are elevated after chronic ethanol consumption, due in part, to induction of a unique isozyme of cytochrome P-450. Production of NADH as a consequence of ethanol oxidation by alcohol dehydrogenase can affect several metabolic functions. NADH was found to be effective as a reductant for the microsomal electron transfer system, and in catalyzing microsomal generation of reactive oxygen species. Acute ethanol (via production of NADH) and chronic ethanol (induction of P-450IIE1, uncoupling) administration may increase microsomal generation of oxygen radicals; the development of oxidative stress in the liver may contribute to the hepatotoxic actions of alcohol.
Cederbaum
A I
AI
Department of Biochemistry, Mount Sinai School of Medicine, NY 10029.
D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity*; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008862:Microsomes, Liver / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D009243:NAD; D013481:Superoxides; D000431:Ethanol; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating