A major goal is to study the toxicity of environmental pollutants, and the interactions of these pollutants with other toxins. One of the most abused toxins is ethanol. Because there is increasing evidence to link alcohol consumption with carcinogenesis, the overall objective of this proposal is to study the metabolism (fate and effect) of a variety of environmental toxins from industrial sources as a function of chronic ethanol ingestion. Studies will be carried out to correlate various metabolic alterations that result from chronic alcohol consumption, i.e., changes in cytochrome P-450 isoenzyme population, changes in the lipid environment upon which critical membrane-protein interactions of the microsomes are dependent, increased production of oxyradicals that contribute to the alterations of lipid membranes, with the metabolic fate and effects of industrial pollutants that lead to carcinogenesis. To this end, enzyme fractions (S9, microsomal and purified) from chronic ethanol-fed rats will be compared with pair-fed controls in the Ames test for their relative abilities to activate several EPA priority pollutants known to be of significant exposure to the industrial work force where alcohol consumption is high. The studies will attempt to determine which of the various alcohol mediated alterations are most important in the carcinogenic action of industrial pollutants by assessing the individual roles of mixed-function oxidase activity, bioreductants, i.e., oxidoreductases and oxyradicals. The differential effects of specific P-450 inhibitors, competing substrates, specific chelating agents that augment or inhibit the iron-catalyzed Haber-Weiss reaction, competing hydroxyl radical scavengers, enzymes such as catalase and superoxide dismutase as well as antioxidants will be compared and contrasted in alcohol-fed vs. pair-fed rats. Using difference spectroscopy, the relative capacity of alcohol-induced microsomes to activate promutagens and to deactivate direct-acting mutagens will be compared with that of microsomes induced by other agents. New information concerning the role of alcohol-consumption in mediating the carcinogenic action of industrial pollutants will be gained and thus, may prove of value in understanding the ramifications of alcohol ingestion in conjunction with exposure to such pollutants.
