Striking differences in the tumorigenic and mutagenic activities of the stereoisomers of benzo(a)pyrene diol epoxide, methylated and un-methylated derivatives of chrysene and benz(a)anthracene bay-region diol epoxides have been observed. In this project, the reaction mechanisms of these stereoisomeric or structurally related polycyclic aromatic hydrocarbon metabolite model compounds with nucleic acids, and the structure of the covalent adducts formed, are investigated utilizing several different spectroscopic techniques. The nucleic acids studied include synthetic polynucleotides, supercoiled DNA, native linear DNA, and oligonucleotides of well-defined base composition and base sequence. The biophysics methods utilized include kinetic flow linear dichroism, fluorescence, circular dichroism, optical detection of magnetic resonance, and nuclear magnetic resonance techniques. The chemical nature of the adducts are studied utilizing standard methods of digestion, chromatographic separation, and analysis of the isolated carcinogen-based adducts. The goal is to establish whether there are any systematic differences either in the mode of reaction, or in the structures and properties of the covalent adducts which are formed when different, biologically active and inactive polycyclic aromatic diol epoxide derivatives interact with DNA. Two types of adducts have been observed up til now. One of them involves a covalent, quasi-intercalative carcinogen-base stacking interaction, and the other involves an adduct with an apparent external conformation. The latter appears to be formed predominantly when the biologically more active diol epoxide derivatives bind to double-stranded DNA. The structural properties of these two types of carcinogen-nucleic acid adducts are being investigated in detail with the goal of obtaining a better understanding of the mechanisms of induction of mutations on a molecular level.
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