Cirrhosis of the liver is a serious pathological manifestation of alcohol abuse. Although effects of ethanol on various aspects of hepatic function have been studied extensively, the specific causes of alcoholic liver disease are not understood. One proposed mechanism is that free radicals may be generated after ethanol exposure. Ethanol has been shown to be metabolized to a free radical intermediate, the 1-hydroxyethyl radical, and lipid radicals have been detected after ethanol administration to experimental animals, using spin trapping techniques. The working hypothesis upon which this proposal is based is that the 1-hydroxyethyl radical initiates a cascade of cellular free radical reactions which ultimately lead to the formation of lipid radicals, lipid peroxidation, and other toxic manifestations of ethanol abuse. The scientific literature indicates that oxygen radicals may have a role in the development of alcoholic liver disease, and results obtained during the current project have proven that the hydroxyl radical has a role in the metabolism of ethanol to the 1hydroxyethyl radical in liver microsomes. This research will probe mechanisms which lead to the formation of free radical intermediates of ethanol and oxygen, particularly the origin of the hydroxyl radical, after acute or long-term alcohol administration. Nutritional, physiological, and pharmacological interventions which may promote, or antagonize, alcohol-induced free radical generation will be characterized. Finally, the physiological consequences of the radicals will be investigated by assessing biochemical changes in the liver under conditions found to intensify the generation of these highly reactive intermediates. The long-term goal of this research is to utilize spin trapping. techniques to evaluate the roles of free radicals in alcoholic injury. This information should be useful for the development of methods to minimize liver injury in those individuals who have not gained control over their compulsion to abuse alcohol. Improved treatment methods may also result from this research. On a broader scale, free radicals are thought to have a role in many different types of pathological conditions, so that a better understanding of their role in promoting tissue injury should provide basic information needed for other health problems.
