Interaction of alcohol with other drugs and nutrients. Implication for the therapy of alcoholic liver disease.
Two decades of research in ethanol metabolism have culminated in the molecular elucidation of an ethanol-inducible cytochrome P450 (P450IIE1) which is not only involved with ethanol metabolism and ethanol tolerance, but also with the activation of a number of xenobiotics. The unique ability of P450IIE1 to activate xenobiotic agents now appears to be responsible for the increased susceptibility of the heavy drinker to hepatotoxic industrial solvents, commonly used drugs, over-the-counter medications and chemical carcinogens. It also explains some of the interaction of ethanol with nutritional factors, such as hepatic vitamin A: enhanced microsomal degradation of retinoids (together with hepatic mobilisation) promotes depletion. Treatment, however, is complicated by the fact that ethanol also enhances the toxicity of excess vitamin A. All pathways of ethanol metabolism result in the production of acetaldehyde, the toxicity of which has been reviewed (Lieber 1982). New aspects discussed here include the formation of acetaldehyde-protein adducts and an associated immune response that may play a pathogenic role. Also discussed are the implications of ethanol-induced alterations in microtubules, mitochondria and plasma membranes, as they relate, in part, to accompanying acetaldehyde-induced toxicity, to the production of free radicals or to lipid peroxidation-mediated injury associated with glutathione depletion. There is also depletion of S-adenosyl-L-methionine (SAMe). Administration of synthetic SAMe results in a partial correction of the SAMe depletion and a consequent restoration of glutathione levels. Other beneficial effects of SAMe include a significant attenuation of the increase in plasma aspartate transaminase and glutamate dehydrogenase activities. Mitochondrial damage, including giant forms, documented by light and electron microscopy, is also attenuated by SAMe. Thus, the new understanding of the pathophysiology of alcohol-induced liver damage has led to more successful therapy with drugs and nutritional factors.
Lieber
C S
CS
Section of Liver Disease and Nutrition, Bronx Veterans Affairs Medical Center, New York.
D000818:Animals; D004044:Dietary Proteins / Q000378:metabolism; D004347:Drug Interactions; D000431:Ethanol / Q000378:metabolism*; D006519:Hepatitis, Alcoholic / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism
D004044:Dietary Proteins; D004364:Pharmaceutical Preparations; D014801:Vitamin A; D014810:Vitamin E; D000431:Ethanol