Carcinogenic polycyclic aromatic hydrocarbons (PAH) are known to undergo enzymatic activation to bay region diol epoxide (BRDE) metabolites which bind covalently to nucleic acids in mammalian cells. While there is strong evidence that alkylation of DNA by these reactive metabolites is critical, there remain many uncertainties concerning the specific details of the molecular mechanisms of PAH carcinogenesis. This proposal is directed towards elucidation of several key mechanistic questions: (i) Is the intercalation of BRDEs into the DNA helix essential or incidental to the mechanism of PAH carcinogenesis? (ii) What is the molecular basis of the remarkable enhancing effect of methyl substitution in nonbenzo ring bay region positions on carcinogenicity (e.g. DMBA and 5-methylchrysene compared to BA and chrysene)Delta (iii) Does the mode of covalent binding to DNA of the BRDEs of the most potent carcinogenic PAH differ significantly with respect to extent of reaction, regio- and stereospecificity of base site attack, the structures of the adducts formed, etc. from that of the BRDEs of biologically less active PAH? Prior investigations of the interaction of the activated BRDE metabolites of PAH have been limited mainly to the BRDE derivatives of benzo[a]pyrene. Since these reactions relatively complex, it is important to distinguish details of the reaction pathway which are critical from those which are irrelevant to bioactivity. Specifically, it is proposed to synthesize the dihydrodiol and BRDE metabolites of a series of 1-alkyl-BaP compounds (R = Me, Et, i-Pr, t-Bu), 5-methylchrysene, 11-methylbenzo[a]pyrene, and 3-methylcholanthrene. The (+)- and (-)enantiomers of the dihydrodiols will be resolved and converted to the corresponding optically pure BRDEs. These compounds will be employed as standards for metabolism studies and their reactions with DNA will be investigated to determine relative extents of reaction, regio- and sterospecifity of attack on the DNA helix, and the structures of the DNA adducts. The findings will be related to the molecular structures and tumorigenicities of these metabolites and the parent PAH.
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