The primary goal has been the elucidation of the structures of reactive metabolites which are responsible for the carcinogenic, cytotoxic and mutagenic activity of polycyclic aromatic hydrocarbons. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for mutagenicity of the synthetic metabolites, iv) elucidation of the roles of the cytochrome P-450 system and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the reaction rates and nature of the products formed by arene oxides and diol epoxides upon reaction with biopolymers and model compounds, and vii) search for agents capable of preventing the tumorigenic action of active metabolites. Current chemical studies have included a new synthesis of oxepins which form during the preparation of benzo-ring arene oxides from dibromoacetate precursors. In selected cases, predictable from PMO calculations, the arene oxides undergo facile photorearrangements to the same oxepins. Studies of the pH dependent solvolysis of precocene I 3,4-oxide have established an unprecedented change in rate determining step from formation of a carbocation intermediate (low pH) to capture of the carbocation by solvent (high pH). Examination of the nucleotide - catalyzed hydrolysis of benzo(a)pyrene 7,8-diol 9,10-epoxide established the importance of stacking interactions between the nucleotide and the hydrocarbon in this general-acid (phosphate) catalyzed process. Stereoselective metabolism of triphenylene to triphenylene 1,2- oxide enantiomers was shown to be dependent on the cytochrome P- 450 preparation utilized. Tumor studies established that introduction of a 6-fluoro substituent into the highly tumorigenic benzo(a)pyrene 7,8-diol 9,10-epoxide eliminates carcinogenic activity, possibly due to a conformational change.
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