Ralston S L, Lau H H, Seidel A, Luch A, Platt K L, Baird W M
Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, Indiana 47907.
Cancer Res. 1994 Feb 15;54(4):887-90.
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.
二苯并[a,l]芘（DB[a,l]P）是一种环境碳氢化合物，在啮齿动物生物测定中是一种非常强效的致癌物，它可以通过形成三种不同的区域异构体海湾或峡湾区域二醇环氧化物或其他更高氧化态的代谢物，在细胞中被激活为与DNA结合的中间体。通过分析[35S]硫代磷酸酯后标记、固定化硼酸酯色谱法和高效液相色谱法形成的DB[a,l]P-DNA加合物，阐明了人乳腺癌细胞系MCF-7中DB[a,l]P的代谢激活机制。检测到六种DB[a,l]P-DNA加合物。将其与DB[a,l]P-11,12-二醇在细胞中形成的加合物以及DNA与顺式和反式（分别为苄基羟基和环氧基氧顺式和反式）DB[a,l]P-11,12-二醇-13,14-环氧化物（DB[a,l]PDE）反应形成的加合物进行比较，结果表明MCF-7细胞中所有的DB[a,l]P-DNA加合物均由这些二醇环氧化物异构体形成。细胞DNA含有大量的两种顺式和一种反式DB[a,l]PDE-DNA加合物以及少量的一种顺式和两种反式DB[a,l]PDE-DNA加合物。人类细胞将DB-[a,l]P激活为其峡湾区域11,12-二醇13,14-环氧化物的能力表明，环境暴露于DB[a,l]P可能对人类构成风险。
