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

• Published in: Chemical research in toxicology 1997-06, Vol.10 (6), p.687-693
• Main Authors: Ralston, Sherry L, Coffing, Stephanie L, Seidel, Albrecht, Luch, Andreas, Platt, Karl-Ludwig, Baird, William M
• Format: Article
• Language: English
• Subjects: Animals; Benzopyrenes - chemistry; Benzopyrenes - metabolism; Benzopyrenes - toxicity; Breast Neoplasms - metabolism; Carcinogens - metabolism; Carcinoma - metabolism; Cells, Cultured; Cricetinae; Cricetulus; Dihydroxydihydrobenzopyrenes - chemistry; Dihydroxydihydrobenzopyrenes - metabolism; DNA Adducts - chemistry; DNA Adducts - toxicity; Epoxy Compounds - chemistry; Epoxy Compounds - metabolism; Humans; Mutagenicity Tests
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx9700275

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 (+)-syn-DB[a,l]P-11,12-diol 13,14-epoxides (DB[a,l]PDE) which both bind extensively 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. Racemic DB[a,l]P-11,12-dihydrodiol and the two individual (+)- and (−)-enantiomers, the metabolic precursors of the stereoisomeric fjord region dihydrodiol 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)-dihydrodiol 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 exclusively (−)-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-dihydrodiol enantiomers, and this may play an important role in the metabolic activation of the strong carcinogen DB[a,l]P in human cells.