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Comparison of Cytochrome P450- and Peroxidase-dependent Metabolic Activation of the Potent Carcinogen Dibenzo[a,l]pyrene in Human Cell Lines

Formation of Stable DNA Adducts and Absence of a Detectable Increase in Apurinic Sites¹

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907 [V. J. M-C., W. M. B.]; Departments of Environmental and Molecular Toxicology and Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331 [V. J. M-C., W. M. B.]; Institute of Toxicology and Environmental Hygiene, Technical University of Munich, D-80636 Munich, Germany [A. L.]; and Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany [A. S.]

The potent carcinogen dibenzo[a,l]pyrene (DB[a,l]P) has been reported to form both stable and depurinating DNA adducts upon activation by cytochrome P450 enzymes and/or cellular peroxidases. Only stable DB[a,l]P-DNA adducts were detected in DNA after reaction of DB[a,l]P-11,12-diol-13,14-epoxides in solution or cells in culture. To determine whether DB[a,l]P can be activated to metabolites that form depurinating adducts in cells with either high peroxidase (human leukemia HL-60 cell line) or cytochrome P450 activity (human mammary carcinoma MCF-7 cell line), cultures were treated with DB[a,l]P for 4 h, and the levels of stable adducts and apurinic (AP) sites in the DNA were determined. DNA samples from DB[a,l]P-treated HL-60 cells contained no detectable levels of either stable adducts or AP sites. MCF-7 cells exposed to 2 µM DB[a,l]P for 4 h contained 4 stable adducts per 10⁶ nucleotides, but no detectable increase in AP sites. The results indicate that metabolic activation of DB[a,l]P by cytochrome P450 enzymes to diol epoxides that form stable DNA adducts, rather than one-electron oxidation catalyzed either by cytochrome P450 enzymes or peroxidases to form AP sites, is responsible for the high carcinogenic activity of DB[a,l]P.

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