Mechanism of ethanol induced hepatic injury.
Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) which contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Induction also results in energy wastage and increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen synthesis, thereby promoting fibrosis.
Lieber
C S
CS
Alcohol Research and Treatment Center, Bronx VA Medical Center, New York.
D000079:Acetaldehyde / Q000633:toxicity; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D009747:Nutritional Physiological Phenomena
D004731:Endotoxins; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde