PHYSICAL AND CHEMICAL INTERACTIONS OF BPDE AND DNA

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Benzo(a)pyrene is converted into a potent chemical carcinogen by cellular metabolism. This intermediate is the 7 beta, 8 alpha- dihydroxy-9 alpha,lO alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE). The active metabolite occurs as four diastereomers the (+)- and (-)-anti- and (+)- and (-)-syn-BPDEs. The most mutagenic and carcinogenic isomer is the (+)-anti-BPDE. We propose to continue our BPDE-DNA studies on two fronts: (i) elucidation of the physical binding and covalent binding mechanisms of the four BPDE diastereomers to natural and synthetic nucleic acid polymers and (ii) to synthesize completely-defined, BPDE-modified oligonucleotides for chemical and physical studies of covalent complexes. We will analyze covalent adduct formation between the syn-BPDEs and DNA. We will determine the reaction mechanisms for binding BPDEs to dAdo and dCyd binding sites in synthetic and naturally occurring polynucleotides. We will synthesize BPDE- modified oligonucleotides, utilizing all four isomers of the carcinogen. The hydrocarbons will be specifically attached to dGuo, dAdo or dCyd sites. These synthetic molecules will be characterized by spectroscopic and sequencing techniques. These site-specific, carcinogen-modified oligonucleotides will be employed in conformational studies. The change in conformation will be assessed for adducts located at different bases and in different sequences. The physical and chemical properties of these modified oligonucleotides will be defined by fluorescence, CD, NMR, and mass spectroscopies and X-ray crystallographic techniques. Physical and chemical properties of the defined lesions will be correlated with the biological properties of these environmentally important polycyclic aromatic hydrocarbons.