ACTIVATION OF POLYCYCLIC ENVIRONMENTAL MUTAGENS

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The objective of this research is to gain insight into chemical carcinogenesis by extending studies on cytochrome P-450 metabolism and nucleic acid adduct formation to polycyclic compounds outside the subset of alternate, bay region polynuclear aromatics heretofore investigated. The polycyclic aromatic compounds to be studied are cyclopenta(cd)pyrene, cholanthrylene, acephenanthrylene, acenaphthylene. The metabolites of these compounds will be separated and characterized and the mutagenic metabolites identified. A model P-450 system will be constructed in which the oxene complex proposed as the intermediate in the enzymatic oxygen transfer will be stabilized. Characterization of the oxene and its reaction with polycyclic substrates will help to elucidate the mechanism of P-450 oxidations. From mechanistic considerations and the electronic structure of the substrates, a structure-reactivity relationship will be developed and then evaluated by comparing predicted metabolic profiles with profiles observed experimentally. The active metabolites, assumed to be the epoxides inferred from the presence of the corresponding dihydrodiols, will be synthesized and their adducts with guanosine characterized. For the oxides, mutagenicity is postulated to be a function of the relative stability of the carbonium ion resulting from acid catalyzed epoxide opening. This structure-reactivity relationship can be evaluated by comparing rate constants and product distributions of acid hydrolysis of the oxides with their mutagenic potency.