The lung possesses significant xenobiotic metabolizing activity which can play a major role in the bioactivation and detoxification of drugs and environmental chemicals especially for those compounds which may exert their pharmacological or toxicological effects locally. Because of the widespread use of ethanol both acutely and chronically it is important to know how it may alter the ability of the lung to metabolize drugs and chemicals. Despite the well-known effects of ethanol on xenobiotic metabolism by the liver, little is known about the lung. While it is generally accepted that the liver is responsible for the metabolism of ethanol and that xenobiotics may alter its metabolism by this organ, little is known about the lung although several studies indicate significant metabolism of ethanol by this organ including non-alcohol dehydrogenase mediated pathways. A major objective of the proposed research is to examine the influence of ethanol on the metabolism and toxicity of chemicals in the lung. A second is to determie the role of the lung in the metabolism of ethanol and the effects of exogenous chemicals on this activity. The ability of ethanol to alter xenobiotic metabolism, both mixed function oxidase and conjugation reactions, will be determined in rats and rabbits and compared with both the effects of ethanol on the liver and the effects of other agents which modify these reactions in the lung. Because of differences in both the pattern of alcohol consumption and the known differences in response of the liver to various administrations of ethanol, single dose, 7 day and 21 day protocols will be compared. Of special interest is the effect of ethanol on the binding and hence toxicity of the toxicants 4-ipomeanol, bromobenzene and carbon tetrachloride. In examining the role of the lung in ethanol metabolism and its perturbation there by xenobiotics, alcohol dehydrogenase, catalase, microsomal ethanol oxidizing system, conjugation reactions and fatty acid ester formation will be determined in both cell fractions and in the isolated perfused rabbit lung. The influence of chemicals known to alter these pathways will be compared with the ability of ethanol to alter its own metabolism in this organ. These studies will determine the importance of the interaction of ethanol with those metabolizing systems in the lung responsible for the activation and detoxification of chemicals and the significance of the role of the lung in ethanol metabolism, the pathways involved and their perturbation by xenobiotics.
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