This research provides an integrated approach to an understanding of the carcinogenic process and its step-wise nature. The studies in the laboratory of Drs. J. A. and E. C. Miller are directed toward further characterization of the electrophilic metabolites of chemical carcinogens, the identification of the reaction products of these metabolites with cellular macromolecules, and correlations of specific reactions with the likelihood of tumor initiation. Dr. Kasper's research is focused on a molecular understanding of the biochemical regulation of the activities of certain enzymes (cytochrome P-450, NADPH-cytochrome c (P-450) oxidoreductase, and epoxide hydratase) which are important in the metabolic activation and/or deactivation of a variety of chemical carcinogens. cDNA probes for these enzymes will be used to determine the effects of xenobiotic chemicals on nuclear and cytoplasmic events related to the induction of these enzymes. The research in Dr. Boutwell's laboratory is directed toward the elucidation of the events involved in tumor promotion that are elicited in mouse skin by application of the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. Of particular importance are studies on the isolation from mouse epidermis of receptors for specific uptake of the phorbol esters and the characterization of these receptors. He is also analyzing the modulation of ornithine decarboxylase activity; induction of this enzyme is an early event after the administration of the phorbol ester and is closely correlated with tumor promotion. Dr. Poland's group is analyzing the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, which are mediated through its cytosolic receptor. This agent induces epidermal hyperplasia and hyperkeratosis and promotes skin tumor formation in HRS/J (hr/hr) mice, but not in their haired littermates. Dr. Pitot is analyzing the relationship of the enzyme-altered foci of hepatic parenchymal cells in carcinogen-treated liver to the eventual development of hepatic carcinomas. He is also examining the stability of the phenotypes and the cell biology of the foci cells. This group is also studying the regulation of the synthesis and the stabilization of mRNA for serine dehydratase and ornithine aminotransferase, as an approach to a better understanding of the molecular bases for the differences between normal liver and hepatic carcinomas.
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