Metabolic activation of dibenzo(a,e)fluoranthene, a nonalternant carcinogenic polycyclic hydrocarbon, in liver homogenates.

Dibenzo(a,e)fluoranthene (DBF), a powerful carcinogenic nonalternant aromatic hydrocarbon, has been metabolized in vitro by incubation in mouse and rat liver microsomal homogenates. Five major stable metabolites were separated by highpressure liquid chromatography and then analyzed by spectroscopic procedures and comparison with synthetic model com pounds. Three of them are phenols corresponding to hydroxylation of DBF at positions 3, 4, and 7. The two others are dihydrodiols. The proposed structures and conformations as established by proton magnetic resonance are frans-3,4 dihydro-3,4-dihydroxyand frans-12,13-dihydro-12,13-dihydroxydibenzo(a,e)fluoranthene. With the exception of 7-hydroxydibenzo(a,e)fluoranthene, all these metabolites correspond to the benzanthracenic part of DBF. However, no metabolite of the substituted "pseudo K region" was observed. The dihydrodiols may be considered as potential precursors of vicinal diol-epoxides which could be formed in a second step of the metabolic activation pathway leading to cell transformation. Quantomechanical calculations have been carried out in order to estimate the relative reactivity of such diol-epoxides. They predict a maximum reactivity for the derivatives formed on the benzenoid E ring of DBF. However, the formation of these two diol-epoxides is hardly predictable from our experi mental observations. Among the metabolites of the benzan thracenic part, the vicinal diol-epoxide of the "bay region" is still predicted as the most reactive one and could be the ultimate metabolite of this nonalternant polycyclic hydrocar bon.