STEREOSELECTIVE ACTIVATION OF DIBENZO[A,L]PYRENE AND ITS TRANS-11,12-DIHYDRODIOL TO FJORD REGION 11,12-DIOL 13,14-EPOXIDES IN A HUMAN MAMMARY-CARCINOMA MCF-7 CELL-MEDIATED V79 CELL MUTATION ASSAY

Dibenzo[a,l]pyrene (DB[a,l]P) represents the most potent carcinogenic polycyclic aromatic hydrocarbon (PAH) yet discovered. Like other PAHs, DB[a,l]P requires metabolic activation to exert its mutagenic and/or carcinogenic activity. In the human mammary carcinoma cell line MCF-7, DB[a,l]P is stereoselectively metabolized to the (-)-anti- and (+)-sy n-DB[a,l]P-11,12-diol 13,14-epoxides (DB[a,l]PDE) which both bind exte nsively to deoxyadenosine residues in DNA. To further characterize the underlying mechanism of its strong carcinogenicity, the relationship between DNA binding and mutagenicity of DB[a,l]P was determined. Racem ic DB[a,l]P-11,12-dihydrodiol and the two individual (+)- and (-)-enan tiomers, the metabolic precursors of the stereoisomeric fjord region d ihydrodiol epoxides, were also investigated. Induction of mutations at the HPRT locus was measured in a MCF-7 cell-mediated Chinese hamster V79 cell mutation assay. The parent hydrocarbon, (+/-)-DB[a,l]P-11,12- dihydrodiol, and (-)-DB[a,l]P-11,12-dihydrodiol were highly mutagenic under the assay conditions. In contrast, (+)-DB[a,l]P-(11S,12S)-dihydr odiol was not mutagenic using MCF-7 cells as the metabolic activating system. Analysis of DNA adducts in the same experiments revealed that MCF-7 cells treated with (-)-DB[a,l]P-11,12-dihydrodiol formed exclusi vely (-)-anti-DB[a,l]PDE adducts whereas cells treated with (+)-DB[a,l ]P-11,12-dihydrodiol did not contain detectable levels of DNA adducts, These results suggest that specific cytochrome P450 enzymes may have high stereoselectivity for activation of the two DB[a,l]P-11,12-dihydr odiol enantiomers, and this may play an important role in the metaboli c activation of the strong carcinogen DB[a,l]P in human cells.