The Potent Carcinogen Dibenzo[a,/]pyrene Is Metabolically Activated to Fjord-Region ll,12-Diol 13,14-Epoxides in Human Mammary Carcinoma MCF-7 Cell Cultures I

Dibenzo[a,/]pyrene (DB[a,/]P), an environmental hydrocarbon and very potent carcinogen in rodent bioassays, could be activated to DNA-binding intermediates in cells through formation of three different regioisomeric bayor fjord-region diol-epoxides or other more highly oxidized metaboUtes. The mechanism of metabolic activation of DB[a,/]P in the human mammary carcinoma cell line MCF-7 was elucidated by analyzing the DB[a,/]P-DNA adducts formed by [3SS]phosphorothioate postlabeling, immobilized boronate chromatography, and high-performance liquid chromatography. Six DB[a,/]P-DNA adducts were detected. Comparison with those formed in cells by DB[a,/]P-11,12-diol and by reaction of DNA with synand anti-(benzylic hydroxyl and epoxide oxygen cis and trans, respectively) DB[a,/]P-11,12-dioi-13,14-epoxide (DB[a,/]PDE) demonstrated that all DB[a,/]P-DNA adducts in MCF-7 cells were formed by these diolepoxide isomers. Cellular DNA contained large amounts of two synand one anti.DB[a,1]PDE.DNA adducts and small amounts of one synand two anti-DB[a,I]PDE-DNA adducts. The ability of human cells to activate DB[a,/]P to its fjord-region ll,12-diol 13,14-epoxides suggests that environmental exposure to DB[a,/]P could pose a risk for humans.