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 cultures.
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.
Ralston
S L
SL
Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, Indiana 47907.
Lau
H H
HH
Seidel
A
A
Luch
A
A
Platt
K L
KL
Baird
W M
WM
D001580:Benzopyrenes / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism*; D002273:Carcinogens / Q000493:pharmacokinetics*; D004247:DNA / Q000378:metabolism; D004852:Epoxy Compounds / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D014407:Tumor Cells, Cultured
D001580:Benzopyrenes; D002273:Carcinogens; D004852:Epoxy Compounds; D004247:DNA; C041517:dibenzo(a,l)pyrene