Biochemical mechanisms of alcohol-induced hepatic injury.
Three decades of research in ethanol metabolism have established that alcohol is hepatotoxic not only because of secondary malnutrition but also through metabolic disturbances associated with the oxidation of ethanol. Some of these alterations are due to redox changes produced by the NADH generated via the alcohol dehydrogenase (ADH) pathway which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone explains the exacerbation of the ethanol-induced lesions in zone III. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450 (P450IIE1) which contributes not only to ethanol metabolism and tolerance, but also to the toxicity of various xenobiotics. Their activation by P450IIE1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatoxicity. Furthermore, induction of the microsomal pathway results in increased acetaldehyde production. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and is associated with a striking impairment of the capacity of the liver to utilize oxygen. Acetaldehyde also promotes glutathione depletion, free-radical mediated toxicity, lipid peroxidation and hepatic collagen synthesis. This new understanding may eventually improve drug and nutritional therapy.
Lieber
C S
CS
Alcohol Research and Treatment Center, Bronx VA Medical Center, New York.
D000079:Acetaldehyde / Q000633:toxicity; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004361:Drug Tolerance; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology; D008862:Microsomes, Liver / Q000378:metabolism
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde