The objectives of this work are (1) to study the reactivities of epoxides and diol epoxides of polycyclic aromatic hydrocarbons with DNA under controlled laboratory conditions, (2) to elucidate the chemical structure, base specificities, and conformations of the covalent carcinogen-DNA adducts formed, and (3) to elucidate the chemical structure and conformation of carcinogen-DNA adducts formed when aromatic hydrocarbon carcinogens react with DNA in tissue culture. It is proposed to identify the major metabolic intermediates of aromatic hydrocarbons by comparing the products of reactions with DNA in whole cells with products obtained by reacting the approprate metabolic intermediates synthesized in the laboratory and subsequently reacted with DNA in aqueous solutions. Once the appropriate in vivo metabolites are identified, their mechanisms of reaction with DNA, including physical intercalation, covalent adduct formation and hydrolysis to tetraols or diols, will be studied in detail in model reaction systems. A combination of physical and chemical techniques are utilized in this work. These include high pressure liquid chromatography for chemical characterization, and spectroscopic techniques such as fluorescence, phosphorescence, optical detection of magnetic resonance, stopped flow absorption and fluorescence, and linear dichroism on oriented samples of DNA for physico-chemical characterization. The immediate goals of this work are to deduce the physical and chemical factors which determine the reactivities of diol epoxide and epoxide derivatves of aromatic hydrocarbons with DNA, and to determine if there are any differences in these properties between bay-region diol epoxides and other structurally related metabolites. In addition, the conformations of carcinogen-DNA adducts are being studied in order to determine if there are any systematic differences between aromatic hydrocarbon-DNA adducts derived from carcinogens and structurally related non-carcinogens. The long range objectives are to obtain an insight into the mechanism of chemical carcinogenesis initiated by polycyclic aromatic hydrocarbon carcinogens.
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