ENVIRONMENTAL COCARCINOGENS--FLUORANTHENE AND PYRENE

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Fluoranthene and pyrene and found throughout the human environment. These polycyclic aromatic hydrocarbons (PAH) are formed together with benzo[a]pyrene (BaP) primarily by incomplete combustion of organic matter. Several studies have demonstrated that fluoranthene and pyrene exert a cocarcinogenic effect on BaP although neither compound is active as a tumor promoter. It has been demonstrated in our laboratory that fluoranthene and pyrene, when applied together with BaP in vivo in mouse skin, lead to increased levels of BaP-DNA adduct formation as compared to BaP alone. The objective of this proposal is to determine the molecular basis for this observation. The effect of fluoranthene and pyrene on the in vivo metabolism of BaP in mouse skin will be determined. These studies will address the question of whether the cocarcinogens induce metabolic activation of BaP in mouse skin or compete for detoxification pathways. The metabolism of fluoranthene and pyrene in vivo in mouse skin will also be studied. Major metabolites will be evaluated for their effect on the in vivo formation of BaP-DNA adducts in mouse skin. The effects of these same metabolites on the in vivo metabolism of BaP in mouse skin will also be determined. The possibility that electrophilic metabolites of fluoranthene and pyrene can bind to mouse skin DNA, RNA, and proteins will be evaluated. Metabolites of fluoranthene and pyrene which lead to increased BaP-DNA adduct formation and electrophilic metabolites found to bind to cellular macromolecules will be assayed for cocarcinogenicity on mouse skin.