Hepatic and metabolic effects of ethanol: pathogenesis and prevention.
Mechanisms of the hepatotoxicity of ethanol are reviewed, including effects resulting from alcohol dehydrogenase (ADH) mediated excessive hepatic generation of NADH and acetaldehyde. Gastric ADH explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some commonly used drugs. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 25 years have culiminated in the molecular elucidation of the ethanol-inducible cytochrome P-450 (2E1) which causes metabolic tolerance to ethanol and to various commonly used medications, enhanced degradation of testosterone and vitamin A (with vitamin A depletion) and selective hepatic perivenular toxicity. The latter results from free radical generation and activation of various xenobiotics, causing increased vulnerability of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A and beta-carotene. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation which promotes GSH depletion and lipid peroxidation and other toxic effects. Nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other 'supernutrients' include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates.
Lieber
C S
CS
Alcohol Research and Treatment Center, Bronx VA Medical Center, New York 10468.
D000079:Acetaldehyde / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000517:prevention & control
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde