Stereoselective activation of dibenzo[a,l]pyrene to (-)-anti (11R,12S,13S,14R)- and (+)-syn(11S,12R,13S,14R)-11,12-diol-13,14-epoxides which bind extensively to deoxyadenosine residues of DNA in the human mammary carcinoma cell line MCF-7.
Dibenzo[a,l]pyrene (DB[a,l]P) is an environmental contaminant and a very potent carcinogen. DB[a,l]P exceeds the carcinogenic potency of both benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in rodent bioassays. Previous studies demonstrated that DB[a,l]P is metabolized to DB[a,l]P-11,12-diol-13,14-epoxide (DB[a,l]PDE) in the human mammary carcinoma cell line MCF-7. In the present study the major DNA adducts formed in DB[a,l]P-treated MCF-7 cells have been identified through the use of 33P-postlabeling. TLC and HPLC. DB[a,l]P is metabolically activated in MCF-7 cells to form large amounts of three major DNA adducts and smaller amounts of three other adducts. The three major DNA adducts are with deoxyadenosine: two are formed by reaction of (+)-syn-DB[a,l]PDE (11S,12R,13S,14R), the third by reaction of (-)-anti-DB[a,l]PDE (11R,12S,13S,14R). The results demonstrate that DB[a,l] is stereoselectively metabolized in MCF-7 cells to form one enantiomer of each diol epoxide diastereomer; (+)-syn-DB[a,l]PDE and (-)-anti-DB[a,l]PDE. The high extent of binding of these diol epoxides to deoxyadenosine in DNA of MCF-7 cells may help to explain the very high carcinogenic potency of DB[a,l]P and suggests that DB[a,l]P could also pose a carcinogenic threat to humans.
Ralston
S L
SL
Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Seidel
A
A
Luch
A
A
Platt
K L
KL
Baird
W M
WM
D001580:Benzopyrenes / Q000493:pharmacokinetics*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D018736:DNA Adducts; D004273:DNA, Neoplasm / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism*; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D006801:Humans; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D001580:Benzopyrenes; D018736:DNA Adducts; D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D004101:Dihydroxydihydrobenzopyrenes; C041517:dibenzo(a,l)pyrene