Melendez-Colon V J, Luch A, Seidel A, Baird W M
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
Cancer Res. 1999 Apr 1;59(7):1412-6.
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,I]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 microM DB[a,l]P for 4 h contained 4 stable adducts per 10(6) 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.
据报道，强效致癌物二苯并[a,l]芘（DB[a,l]P）在细胞色素P450酶和/或细胞过氧化物酶的激活作用下，会形成稳定的和导致嘌呤脱落的DNA加合物。在DB[a,l]P - 11,12 - 二醇 - 13,14 - 环氧化物与溶液或培养细胞反应后，仅在DNA中检测到稳定的DB[a,l]P - DNA加合物。为了确定DB[a,l]P是否能被激活形成在具有高过氧化物酶活性（人白血病HL - 60细胞系）或细胞色素P450活性（人乳腺癌MCF - 7细胞系）的细胞中导致嘌呤脱落的加合物的代谢物，用DB[a,l]P处理细胞培养物4小时，然后测定DNA中稳定加合物和脱嘌呤（AP）位点的水平。来自经DB[a,l]P处理的HL - 60细胞的DNA样品中未检测到稳定加合物或AP位点的可检测水平。暴露于2 microM DB[a,l]P 4小时的MCF - 7细胞每10(6)个核苷酸含有4个稳定加合物，但AP位点没有可检测到的增加。结果表明，细胞色素P450酶将DB[a,l]P代谢活化为形成稳定DNA加合物的二醇环氧化物，而不是细胞色素P450酶或过氧化物酶催化的单电子氧化形成AP位点，是DB[a,l]P高致癌活性的原因。
