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.

Abstract

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.

• Authors: S L Ralston, S L Coffing, A Seidel, A Luch, K L Platt, W M Baird
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 10 Issue 6 Pg. 687-93 (Jun 1997) ISSN: 0893-228X [Print] United States
• PMID: 9208176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrenes
• Carcinogens
• DNA Adducts
• Dihydroxydihydrobenzopyrenes
• Epoxy Compounds
• 11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo(a,l)pyrene
• dibenzo(a,l)pyrene 11,12-dihydrodiol
• dibenzo(a,l)pyrene

Topics

• Animals
• Benzopyrenes (chemistry, metabolism, toxicity)
• Breast Neoplasms (metabolism)
• Carcinogens (metabolism)
• Carcinoma (metabolism)
• Cells, Cultured
• Cricetinae
• Cricetulus
• DNA Adducts (chemistry, toxicity)
• Dihydroxydihydrobenzopyrenes (chemistry, metabolism)
• Epoxy Compounds (chemistry, metabolism)
• Humans
• Mutagenicity Tests