Metabolic activation of benzo[c]phenanthrene by cytochrome P450 enzymes inhuman liver and lung

The environmentally occurring polycyclic aromatic hydrocarbon (PAH) benzo [ c]phenanthrene (B[c]PH) is a weak carcinogen in rodents. In contrast, the d ihydrodiol-epoxides of B[c]PH are among the most carcinogenic PAH metabolit es tested so far. In rodents, B[c]PH is predominantly metabolized to B[c] P H-5,6-dihydrodiol (B[c]PH-5,6-DH) and only to a minor extent to B[c]PH-3,4- DH, the proximate precursor of the highly potent ultimate carcinogen, B[c]P H-3,4-DH-1,2-epoxide. This might explain why in rodents B [c] PH is a weak carcinogen. However, little is known about human metabolism of B[c]PH Using microsomal preparations from human liver and lung, we investigated the met abolic activation of B[c]PH. In contrast to the findings in experimental an imals, human liver microsomes predominantly generated B[c]PH-3,4-DH and onl y to a minor extent B[c]PH-5,6-DH. Only one lung tissue sample was found to be metabolically active, producing B[c]PH-5,6-DH together with small amoun ts of B[c]PH-3,4-DH. Catalytic activities known to be associated with speci fic cytochrome P450 (P450) enzyme activities were determined and correlated with the spectrum of B [c] PW metabolites. The results indicate that B[c]P H-DIR formation in human liver is mainly mediated by P450 1A2. Studies with P450 enzyme selective inhibitors confirmed these findings. Further support was obtained using preparations of the respective human recombinant P450 e nzymes expressed in Escherichia coli and yeast. In addition to P450 1A2, P4 50 1B1 effectively mediated B [c] PII-metabolism. The umu-assay for inducti on of SOS repair response in Salmonella typhimurium TA 1535 pSK 1002 contai ning a umuC-lacZ reporter gene was used to study metabolic generation of ge notoxic metabolites from B[c]PH-DHs in human microsomal preparations. B[c]P H-3,4-DH was activated by human liver microsomes to a potent genotoxic agen t. Taken together, the results clearly demonstrate that human liver microso mes can effectively catalyze the biotransformation of B[c]PH into highly ge notoxic metabolites. The results provide evidence that B[c]PH should be con sidered a potentially potent carcinogen in humans, and that rodent models m ay underestimate the risk.