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Alcoholic cirrhosis of the liver is a serious consequence of long-term alcohol abuse. Although alcohol causes many changes in normal liver function, the specific causes of alcoholic liver disease are not understood. One proposed mechanism is that free radicals generated after acute and chronic alcohol consumption may be responsible for initiating liver injury. This hypothesis will be tested by using the spin trapping method and EPR spectroscopy to detect and identify radicals formed in rats which have been exposed to alcohol. In the first specific aim, Wistar rats will be fed alcohol by continuous intragastric infusion, along with liquid diets which contain one of three types of dietary fat. When fish oil is the source of fat, rats develop severe liver necrosis within four weeks, while more moderate injury is observed when the diet contains corn oil. If saturated fat is fed along with alcohol, fatty liver develops, but more serious forms of liver injury are absent. Rats fed the liquid diets with dextrose in place of alcohol do not develop liver disease. Radicals which are detected in livers from rats fed these dietary regimens will be characterized and compared with histological evaluation of the tissue to determine the relationship between radical formation and liver injury. In the second specific aim, inhibitors and antioxidants will be used to probe mechanisms which regulate formation of 1hydroxyethyl radicals and lipid radicals in the liver. These experiments will be conducted vhth acute alcohol administration to untreated rats, as well as to rats fed liquid alcohol or control diets. Additional experiments will be performed to determine the fraction of alcohol which is metabolized through a free radical pathway, and to assess the role that acetaldehyde may have in initiating free radical reactions. Finally, salicylate and D-phenylalanine will be administered to rats to test whether hydroxyl radical formation is increased after acute or chronic alcohol administration. Data from these studies will help to define roles that radicals have in alcoholic-liver injury, and may lead to development of preventative measures.
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