King L C, Adams L, Allison J, Kohan M J, Nelson G, Desai D, Amin S, Ross J A
Biochemistry and Pathobiology Branch, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Mol Carcinog. 1999 Oct;26(2):74-82.
Dibenzo[a,l]pyrene (DB[a,l]P), an extremely potent environmental carcinogen, is metabolically activated in mammalian cells and microsomes through the fjord-region dihydrodiol, trans-DB[a,l]P-11, 12-diol, to syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides (syn- and anti-DB[a,l]PDEs). The role of seven individual recombinant human cytochrome P450s (1A1, 1A2, 1B1, 2B6, 2C9, 2E1, and 3A4) in the metabolic activation of DB[a,l]P and formation of DNA adducts was examined by using (32)P postlabeling, thin-layer chromatography, and high-pressure liquid chromatography. We found that, in the presence of epoxide hydrolase, only P450 1A1 and P450 1B1 catalyzed the formation of DB[a,l]PDE-DNA adducts and several unidentified polar adducts. Human P450 1A1 catalyzed the formation of DB[a, l]PDE-DNA adducts and unidentified polar adducts at rates threefold and 17-fold greater than did human P450 1B1 (256 fmol/h/nmol P450 versus 90 fmol/h/nmol P450 and 132 fmol/h/nmol P450 versus 8 fmol/h/nmol P450, respectively). P450 1A1 DNA adducts were derived from both anti- and syn-DB[a,l]PDE at rates of 73 fmol/h/nmol P450 and 51 fmol/h/nmol P450, respectively. P450 1B1 produced adducts derived from anti-DB[a,l]PDE at a rate of 82 fmol/h/nmol, whereas only a small number of adducts were derived from syn-DB[a,l]PDE (0.4 fmol/h/nmol). These results demonstrated the potential of human P450 1A1 and P450 1B1 to contribute to the metabolic activation and carcinogenicity of DB[a,l]P and provided additional evidence that human P450 1A1 and 1B1 differ in their stereospecific activation of DB[a,l]P. Mol. Carcinog. 26:74-82, 1999. Published 1999 Wiley-Liss, Inc.
二苯并[a,l]芘（DB[a,l]P）是一种极具活性的环境致癌物，在哺乳动物细胞和微粒体中通过峡湾区二氢二醇，即反式-DB[a,l]P-11,12-二醇，代谢活化为顺式和反式-DB[a,l]P-11,12-二醇-13,14-环氧化物（顺式和反式-DB[a,l]PDEs）。通过使用³²P后标记、薄层色谱法和高压液相色谱法，研究了七种单独的重组人细胞色素P450（1A1、1A2、1B1、2B6、2C9、2E1和3A4）在DB[a,l]P代谢活化及DNA加合物形成中的作用。我们发现，在环氧水解酶存在的情况下，只有P450 1A1和P450 1B1催化形成DB[a,l]PDE-DNA加合物和几种未鉴定的极性加合物。人P450 1A1催化形成DB[a,l]PDE-DNA加合物和未鉴定的极性加合物的速率分别比人P450 1B1快三倍和十七倍（分别为256 fmol/h/nmol P450对90 fmol/h/nmol P450以及132 fmol/h/nmol P450对8 fmol/h/nmol P450）。P450 1A1的DNA加合物分别以73 fmol/h/nmol P450和51 fmol/h/nmol P450的速率来自反式和顺式-DB[a,l]PDE。P450 1B1以82 fmol/h/nmol的速率产生源自反式-DB[a,l]PDE的加合物，而只有少量加合物源自顺式-DB[a,l]PDE（0.4 fmol/h/nmol）。这些结果证明了人P450 1A1和P450 1B1在DB[a,l]P代谢活化和致癌性方面的潜在作用，并提供了额外证据表明人P450 1A1和1B1在DB[a,l]P的立体特异性活化方面存在差异。分子致癌作用。26:74 - 82，1999年。1999年由威利 - 利斯公司出版。
