Metabolism of ethanol and associated hepatotoxicity

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Over the last three decades, direct hepatotoxic effects of ethanol were established, some of which were linked to redox changes produced by NADH generated via the alcohol dehydrogenase (ADH) pathway and shown to affect the metabolism of lipids, carbohydrates, proteins, and purines. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450; this newly discovered ethanol-inducible cytochrome P-450 (P-450 IIEi) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P-450IIEi now provides an understanding of the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, and chemical carcinogens. P-450 induction also explains depletion (and toxicity) of nutritional factors such as vitamin A. As a consequence, treatment with vitamin A and other nutritional factors is beneficial, but must take into account a narrowed therapeutic window in alcoholics who have increased needs for nutrients and also display an enhanced susceptibility to some of their adverse effects. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts, and causes glutathione depletion. Supplementation with S-adenosyl-L-methionine partly corrects the depletion and associated mitochondrial injury, whereas administration of polyunsaturated lecithin opposes the fibrosis. Thus, at the cellular level, the classic dichotomy between the nutritional and toxic effects of ethanol has now been bridged. The understanding of how the ensuing injury eventually results in irreversible scarring or cirrhosis may provide us with improved modalities for treatment and prevention.