Metabolic activation of chrysene by human hepatic and pulmonary cytochrome P450 enzymes

The metabolic activation of chrysene, a weak carcinogen found in tobacco smoke, gasoline engine exhaust, and other environmental sources was analyzed in 18 human hepatic and 11 pulmonary microsomal samples. The major metabolites formed were 3,4-dihydroxy-3,4-dihydrochrysene (chrysene-3,4-diol), chrysene-1,2-diol and to lower extents phenols. Chrysene-5,6-diol was found in trace amounts only. All human liver samples formed the proximate carcinogen chrysene-1,2-diol (1.3-5.8 pmol/mg protein/min). Comparable results were seen with pulmonary microsomes, but metabolites were formed to about 10 fold lower extents. Here the most prominent metabolite was chrysene-1,2-diol. Catalytic activities known to be associated with specific cytochrome P450s were determined and correlated with the levels of metabolites formed in each sample. The results of the correlation analysis as well as studies with the inhibitor α-naphthoflavone indicated that hepatic cytochrome P450 1A2 plays a major role in the formation of the proximate carcinogen chrysene-1,2-diol and most of the other metabolites. The formation of metabolites in human lung seems mainly to be due to cytochrome P450 1A1 activity. These results demonstrate that cytochrome-P450 1A mediated metabolic activation processes occur for chrysene in human liver and lung.