Oxygen can be toxic to cells when it is transformed into reactive intermediates called oxygen radicals. Many agents damage cells by promoting the production of oxygen radicals and lipid peroxidation. The mechanism(s) by which alcohol damages the liver is not understood. Based upon recent results, it appears that alcohol can promote the production of oxygen radicals and induce lipid peroxidation. The specific objective is to evaluate the interaction between alcohol and oxygen radicals in promoting liver cell damage and in increasing the susceptibility of the alcoholic to oxidative stress and to the toxicity of other agents. This information may be of value in preventing or ameliorating some of the toxic effects associated with alcohol abuse. Experiments will be conducted to extend previous observations that production of hydroxyl radicals (.OH) by microsomes from chronic ethanol-fed rats is increased. Rates of superoxide, hydrogen peroxide, .OH production and lipid peroxidation by microsomes from ethanol-treated rats and controls will be determined. Sensitivity to superoxide dismutase, catalase, iron chelators and the role of different iron chelates will be assessed as will the microsomal enzymes which participate in generating oxy-radicals. The activation of compounds which become toxic because of increased generation of oxy-radicals and promotion of lipid peroxidation will be studied. The generation of .OH and promotion of lipid peroxidation by intact hepatocytes will also be evaluated. The overall objective will be to extend studies with microsomal systems to intact cells. Special emphasis will be placed on use of dimethylsulfoxide, tert butyl alcohol and benzoate, as new chemical probes for the detection of .OH-like species. Viability will be monitored to determine if the alcohol-derived cells are especially sensitive to damage by the generated oxy-radicals. Some in vivo experiments to detect .OH and lipid peroxidation after ethanol treatment will be carried out. The regulation of drug metabolism by intact liver cells, the effects produced by acute and chronic ethanol on hepatic drug metabolism, and the role of acetaldehyde in the actions of ethanol will be studied. NADPH availability may regulate oxygen radical generation, and alcohol-drug interactions may explain why alcoholics show different sensitivities to drugs, and are more susceptible to damage by external toxins.
