A substantial body of evidence exists to support the contention that ROS generated during ethanol metabolism may be involved in the pathogenesis of alcoholic liver disease (ALD). Decades ago, it was already emphasized by Lieber that the induction of cytochrome P450 is a critical event with respect to the development of ALD , If free radical production and lipid peroxidation play a role in the development of ALD, depletion of dietary antioxidants such as vitamin E or an increase in oxidants such as non-heme iron in the liver, should enhance the ethanol induced liver damage. Indeed, a diet deficient in vitamin E has been shown to reduce hepatic vitamin E stores, increase lipid peroxidation and increase serum transaminase activities after alcohol feeding in rats , Furthermore, iron supplementation in the diet increases ethanol-induced serum transaminase activities, lipid peroxidation and fibrosis , In addition, a significant correlation between hepatic lipid peroxidation, oxidative stress and hepatic morphology is observed with and without iron supplementation [87,88], Part of the mechanism may be related to the ability of ethanol-derived metabolites such as malondialdehyde and 4-hydroxynonenal to directly stimulate Ito-cells to produce collagen , Further evidence for the involvement of free radicals in alcoholic liver disease is supported by the fact that drugs which are metabolized by cytochrome P450 2E1 to free radicals enhance ethanol-induced liver damage. This is seen with Isoniacide , On the other hand, compounds which inhibit cytochrome P4502E1 such as chlomethiazol or diallyl sulfide [90,91], also inhibit lipid peroxidation, radical production and result in an improvement ofhepatic morphology. Obviously, the degree of induction of cytochrome P4502E1 is of predominant importance with respect to ALD. It is, therefore, concluded that the ROS produced by this pathway may be especially important. This induction is diet dependent and enhanced with unsaturated fatty acids such as corn oil and low carbohydrates. In addition, iron, an important compound in the production ofROS, plays a significant role. Iron supplementation increases liver disease and administration of an iron chelator decreases ALD. Although, the administration of vitamin E to rodents inhibits ALD to some extent, data in humans are not very encouraging. The approach of administering vitamin E together with selenium and zinc to patients with alcoholic cirrhosis did show an improvement in mortality, but the number of patients was small ,
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