Multi-step metabolism of the carcinogen dibenzo[a,e]fluoranthene. II. Metabolic pathways

Abstract

The structural identification of nineteen metabolites of dibenzo[a,e]fluoranthene (DBF) obtained by incubation in rat and mouse liver microsomes, allows one to establish a qualitative and semi-quantitative metabolic chart, involving up to three distinct oxidative attacks. The primary steps lead to dihydrodiols on rings A and D and phenols on rings A and E. Secondary vicinal epoxidation of dihydrodiols is a minor route as compared to attack at a second peripheral ring. Even after a third oxidation, one of the peripheral rings A, D and E remains unsubstituted. A model for cytochrome P-450 enzymatic activity which takes into account most of the observations is proposed. It requires that the catalytic site for monooxygenation is 0.6 nm apart from the center of an hydrophobic protein site accommodating one of the unsubstituted peripheral benzenoid rings. both trans diequatorial dihydrodiols of ring A and D corresponding to the 'bay' and 'pseudo bay region'; of DBF appear in the activation pathways for the in vivo carcinogenesis. The ultimate metabolite reacting with DNA is thus, most probably, a vicinal dihydrodiol epoxide of ring A or D. The great complexity of the metabolic chart of DBF as compared to other carcinogenic polycyclic aromatic hydrocarbons leaves also the possibility of sequential reactions at these two distinct sites of the molecule.