Our studies on methylated polynuclear aromatic hydrocarbons (PAH) have shown that the enhancing effect of a bay region methyl group on their carcinogenicity is due to the relatively high reactivity with DNA and exceptional tumorigenicity of a dihydrodiol epoxide metabolite with the epoxide ring and methyl group in the same bay region. These results have led to a better understanding of the structural requirements for carcinogenicity in this class of compounds. This is significant because methylated PAH are always components of combustion product mixtures to which humans are exposed. The estimated annual emission of methylated PAH from mobile sources in the U.S. is 1700 metric tons. In the present proposal, we will extend our research on methylated PAH, as follows: (1) investigate the formation, reactions with DNA, and tumorigenicity of the eight enantiomeric bay region dihydrodiol expoxides of 5-methylchrysene; (2) investigate the structural requirements for physical association with DNA of a series of methylated chrysene and benzo[a]pyrene dihydrodiol epoxides; (3) investigate the role of glutathione conjugation in 5-methylchrysene metabolism and (4) investigate the potential of synthetic carrier-scavenger complexes as inhibitors of PAH carcinogenesis. The goals of this program are to understand the mechanisms by which these compounds cause cancer and to develop practical strategies for preventing their carcinogenic effects.
