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The Potent Carcinogen Dibenzo[a,l]pyrene Is Metabolically Activated to Fjord-Region 11,12-Diol 13,14-Epoxides in Human Mammary Carcinoma MCF-7 Cell Cultures¹

Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, Indiana 47907 [S. L. R., H. H. S. L., W. M. B.], and Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany [A. S., A. L., K. L. P]

³ To whom requests for reprints should be addressed, at Department of Medicinal Chemistry, Hansen Life Sciences Research Building, Purdue University, West Lafayette, IN 47907.

Dibenzo[a,l]pyrene (DB[a,l]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 bay- or fjord-region diol-epoxides or other more highly oxidized metabolites. The mechanism of metabolic activation of DB[a,l]P in the human mammary carcinoma cell line MCF-7 was elucidated by analyzing the DB[a,l]P-DNA adducts formed by [³⁵S]phosphorothioate postlabeling, immobilized boronate chromatography, and high-performance liquid chromatography. Six DB[a,l]P-DNA adducts were detected. Comparison with those formed in cells by DB[a,l]P-11,12-diol and by reaction of DNA with syn- and anti-(benzylic hydroxyl and epoxide oxygen cis and trans, respectively) DB[a,l]P-11,12-diol-13,14-epoxide (DB[a,l]PDE) demonstrated that all DB[a,l]P-DNA adducts in MCF-7 cells were formed by these diol-epoxide isomers. Cellular DNA contained large amounts of two syn- and one anti-DB[a,l]PDE-DNA adducts and small amounts of one syn- and two anti-DB[a,l]PDE-DNA adducts. The ability of human cells to activate DB-[a,l]P to its fjord-region 11,12-diol 13,14-epoxides suggests that environmental exposure to DB[a,l]P could pose a risk for humans.

¹ This work was supported by Grant CA40228 from the National Cancer Institute, Department of Health and Human Services, and by the Deutsche Forschungsgemeinschaft SFB302. S. L. R. was supported by Training Grant T32-CA09634.

² Present Address: Monsanto Agricultural Company, Environmental Health Laboratory, St. Louis, MO 63110.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 5/93. Accepted 1/ 5/94.

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