The objective of this proposal is to determine the modes of metabolic activation of the carcinogenic non-alternate polynuclear aromatic hydrocarbon carcinogens benzo-(b)fluoranthene, benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene, and 2- and 3-methylfluoranthene. The bay region theory of activation of carcinogenic PAH has been shown to apply to several alternate hydrocarbons. Our studies on the metabolic activation of these six non-alternate PAH indicate that there is little or no similarity in their activation pathways. This program has as its overall objective to elucidate the mechanism of activation of these select PAH which are of particular interest because of actual human exposure. Suspect proximate and/or ultimate carcinogenic metabolites of benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene and 2- and 3-methylfluoranthene have been identified from detailed in vitro and in vivo metabolism studies. Those metabolic activation pathways believed to be associated with carcinogenic activity of these PAH will be evaluated by identification of major DNA-adducts formed in vivo in mouse skin, bioassays of suspect proximate and ultimate mutagens, and/or bioassays of select fluoro-substituted analogs. Studies on the metabolic activation of benzo(b)-fluoranthene suggest that multiple sites on this molecule are associated with its carcinogenicity. Fluorescence spectra of isolated DNA adducts as formed in vivo in mouse skin and a limited study on the effect of fluoro-substitution at specific positions of benzo(b) fluoranthene on tumorigenic activity will be employed to elucidate the mechanism(s) of activation associated with its carcinogenicity. These studies will lead to the elucidation of the mechanism of action of several of these carcinogenic non-alternate PAH, which are ubiquitous in the environment.
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