The objective is to elucidate the mechanisms of carcinogenesis of the major classes of polycyclic aromatic hydrocarbons (PAH) at the molecular level. It is proposed to extend our investigations of the role of substituent effects in the metabolic activation and DNA binding of carcinogenic PAH to obtain evidence for the hypothesis that the apparently unique importance of the bay region in carcinogenicity is not soley the exceptional chemical reactivity of the carbocation intermediates generated in this region, but also the steric inhibition of enzymatic detoxification conferred by this crowded molecular region which allows these epoxide intermediates to survive sufficiently long in vivo to alkylate DNA. The findings will be utilized to relate molecular structural factors, steric and electronic, to activation or deactivation of PAH carcinogens and predict the nature of the active metabolites formed for a wide range of substituted and unsubstituted PAH. Specifically, it is proposed to synthesize the active carcinogenic metabolites of a series of PAH for which the active forms are predicted to be sterically hindered arene oxides, diol epoxides, or triol epoxides (dependent upon molecular structural differences). These compounds will be utilized subsequently in studies of PAH metabolism, DNA binding, mutagenicity, and carcinogenicity. The findings will provide evidence for the hypothesis that there are multiple types of active carcinogenic metabolites of PAH, and an essential requirement for the activity in addition to electrophilic reactivity is relative resistance to the action of epoxide hydrase, glutathione-S-transferase, and other detoxifying enzymes. These compounds will also be furnished to other investigators who request them for pertinent biological studies. The findings will provide the information essential to formulation of a comprehensive theory of PAH carcinogenesis. This will make possible accurate prediction of carcinogenic activity of the wide range of PAH compounds which are ubiquitous in the human environment.
Showing the most recent 10 out of 37 publications
