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 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 the synthesis and assignment of absolute configuration of the optically active 5,6-oxides derived from chrysene, 7,12-dimethylbenz(a)anthracene and benzo(c)phenanthrene as well as assignment of absolute configuration of the predominant 1,2-dihydrodiol metabolite from triphenylene. The absolute configurations of the principal 3,4- and 5,6-oxides formed from benzo(c)phenanthrene by cytochrome P-450c have been determined. An NMR method for determining the enantiomeric composition of arene oxides as well as for predicting their absolute configuration by the use of chiral lanthanide shift reagents has been developed. Diastereomeric 6- fluorobenzo(a)pyrene 7,8-diol 9,10-epoxides, which differ in conformation from the unfluorinated analogues, have been synthesized, and a marked effect of conformation of their rates of solvolysis demonstrated. The mechanism of specific inhibition of cytochrome P450c by 2-bromo-4'-nitroacetophenone has been elucidated. The deoxyguanosine and deoxyadenosine adducts formed by alkylation of DNA by 4 optically active benzo(c)phenanthrene 3,4-diol 1,2-epoxides have been characterized and several of these adducts have been identified upon treatment of rodent embryonic cells in culture with the parent hydrocarbon.
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