Metabolism and Mutagenicity of Dibenzo[a,e]pyrene and the Very Potent Environmental Carcinogen Dibenzo[a,l]pyrene

Dibenzo[a,Z] pyrene (DB[a,/]P) is one of the most potent carcinogens ever tested in mouse skin and rat mammary gland. DB[a,/]P is present in cigarette smoke and, presumably, in other environmental pollutants. Metabolism and mutagenicity studies of this compound compared to the weak carcinogen dibenzo[a,e]pyrene (DB[a,e]P) can provide preliminary evidence on its mechanism of carcinogenesis. The mutagenicity of DB[a,/]P, DB[a,e]P, and benzo[a]pyrene (BP) was compared in the Ames assay with Aroclor-induced rat liver S-9. BP was the strongest mutagen. In strain TA100, DB[a,/]P and DB[a,e]P were marginally mutagenic. In strain TA98 both compounds were mutagenic, and DB[a,Z]P induced more than twice as many revertants as DB[o,e]P. The mutagenicity of DB[a,Z]P does not correlate with its carcinogenicity, since DB[a,/]P is a much stronger carcinogen, but a much weaker mutagen, than BP. The NADPH-supported metabolism of DB[a,e]P and DB[a,Z]P was conducted with uninduced and 3-methylcholanthrene-induced rat liver microsomes. Metabolites were analyzed by reverse-phase HPLC and identified by NMR, UV, and mass spectrometry. Uninduced microsomes produced only traces of metabolites with either compound. The major metabolites of DB[a,/]P with induced microsomes were DB[a,/]P 8,9-dihydrodiol, DB[a,Z]P 11,12-dihydrodiol, 7-hydroxyDB[a,Z]P, and a DB[a,/]P dione. The metabolites of DB[a,e]P with induced microsomes were DB[a,e]P 3,4- dihydrodiol, 3-hydroxyDB[a,e]P, 7-hydroxyDB[a,e]P, and 9-hydroxyDB[a,e]P. Some of these metabolites are very useful in assessing possible pathways of activation in the initiation of cancer.