Multi-step metabolism of the carcinogen dibenzo[a,e] fluoranthene. I. Identification of the metabolites from rat microsomes

Abstract

The metabolism of the polycyclic hydrocarbon dibenzo[a,e]fluoranthene (DBF) has been investigated. Two new primary metabolites have been identified by proton n.m.r. as the trans diaxial dihydrodiols of the bay and of the pseudo bay regions of DBF. In addition, twelve new metabolites arising from secondary and tertiary metabolic transformations have been identified. The stereochemistry of eleven of these products has been established by proton n.m.r. spectroscopy. In contrast with other alternant carcinogenic polycyclic hydrocarbons, a vicinal diol epoxidation at the bay region of the trans diequatorial dihydrodiols is a minor reaction relative to attack at distant sites, which leads principally to phenolic derivatives of the dihydrodiols and, with a lower yield, to a bis-dihydrodiol (3,4,12,13-tetrahydro-3,4,12,13-tetrahydroxy-DBF). This offers a possibility of bifunctional metabolic activation in the carcinogenicity of DBF. A catechol of the benzanthracenic moiety of DBF has also be identified, dibenzo[a,e]fluoranthene 3,4-catechol. In summary, all three external rings of DBF can be attacked enzymatically, but apparently ring E does not undergo epoxidation while more usual trans diaxial and diequatorial dihydrodiols, as well as tetraols of rings A and D, were detected.

Synthesis of Potentially Carcinogenic Higher Oxidized Metabolites of Dibenz[a,j]anthracene and Benzo[c]chrysene

“…The major DNA-bound adduct formed by metabolism of the potent carcinogenic hydrocarbon dibenzo[ b,def ]chrysene , was identified as a bis(diol) epoxide arising from a 1,2,8,9-bis(dihydrodiol) of unspecified stereochemistry. A bis(dihydrodiol), namely 3,4,12,13-tetrahydroxy-3,4,12,13-tetrahydrodibenzo[ a , e ]aceanthrylene, has also been identified as the most mutagenic metabolite of dibenzo[ a , e ]aceanthrylene. , Several isomeric phenolic dihydrodiol metabolites were also detected among the metabolites of this hydrocarbon. In the foregoing examples, structural assignments of the higher oxidized metabolites were based almost entirely on spectroscopic evidence, since in most cases syntheses had not been reported and authentic samples were unavailable for comparison.…”