The role of 12 cDNA‐expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans‐7, 8‐dihydrodiol
The role of 12 cDNA‐expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans‐7, 8‐dihydrodiol
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12 种 cDNA 表达的人、啮齿动物和兔细胞色素 P450 在苯并[a]芘和苯并[a]芘反式-7, 8-二氢二醇代谢中的作用
DOI：
10.1002/mc.2940100307
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发表时间：
1994
影响因子：
4.6
通讯作者：
H. Gelboin
中科院分区：
文献类型：
--
作者：
M. Shou;K. Korzekwa;C. Crespi;F. Gonzalez;H. Gelboin
强效致癌物苯并[a]芘（B[a]P）及其代谢物B[a]P反式-7，8-二氢二醇（7，8-diol）需要通过微粒体细胞色素P450（P450 s）进行代谢活化，以产生多种不良生物学效应，包括与DNA结合、毒性、致突变性和致癌性。在本文报告的研究中，我们确定了12个单独的cDNA表达的细胞色素P450在B[a]P和7，8-二醇代谢中的作用。人P450的1A 1和1A 2表达的情况下或存在的环氧化物水解酶（EH）在人淋巴母细胞系，和6人和5啮齿动物和兔P450表达的cDNA与牛痘病毒载体在肝癌细胞系Hep G2。B[a]P代谢产生9种代谢物（3种二醇、3种醌和3种酚），通过高压液相色谱法对其进行分离、鉴别和定量。在人淋巴母细胞中，人1A 1代谢B[a]P的速率是1A 2的4.5倍。EH被证明直接参与B[a]P活化，因为增加EH的量导致较少的7-羟基苯并[a]芘和更多的7，8-二醇形成。在Hep G2细胞中用牛痘病毒载体表达的人P450中，1A 2和2C 9显示出最高的B[a]P代谢活性，2B 6显示出中等活性。小鼠1A 1的P450活性比任何人、兔或啮齿动物的P450活性高40倍，这表明跨物种外推P450活性的潜在陷阱。7，8-二醇的代谢产生6种代谢产物（4种四醇和2种三醇）。在类淋巴母细胞中，人1A 1对7，8-二醇代谢的活性是1A 2的4.2倍。在由牛痘病毒表达的人P450中，1A 2、2 E1和2C 9具有最高活性，2C 8和3A 4显示出中等活性，可将7，8-二醇代谢为二醇环氧化物。同样，小鼠1A 1比任何其他P450都更活跃。在这些研究中，我们确定了单个P450在B[a]P和7，8-二醇代谢和活化中的能力，因此可能会更好地理解P450如何控制多环芳烃的解毒和活化。© 1994 Wiley‐利斯公司
The potent carcinogen benzo[a]pyrene (B[a]P) and its metabolite B[a]P trans‐7, 8‐dihydrodiol (7, 8‐diol) require metabolic activation by the microsomal cytochrome P450s (P450s) to exert several adverse biological effects, including binding to DNA, toxicity, mutagenicity, and carcinogenicity. In the study reported here, we defined the role of each of 12 individual cDNA‐expressed cytochrome P450s in the metabolism of B[a]P and 7, 8‐diol. Human P450s 1A1 and 1A2 were expressed in the absence or presence of epoxide hydrolase (EH) in a human lymphoblastoid cell line, and six human and five rodent and rabbit P450s were expressed from cDNA with vaccinia virus vectors in the hepatoma cell line Hep G2. B[a]P metabolism resulted in nine metabolites (three diols, three quinones, and three phenols), which were separated, identified, and quantitated by high‐pressure liquid chromatography. In the human lymphoblastoid cells, human 1A1 metabolized B[a]P at a rate 4.5 times greater than that for 1A2. EH was shown to be directly involved in B[a]P activation, since increasing the amount of EH resulted in less 7‐hydroxybenzo[a]pyrene and more 7, 8‐diol formation. Of the human P450s expressed with the vaccinia virus vectors in Hep G2 cells, 1A2 and 2C9 showed the highest activity and 2B6 showed moderate activity for B[a]P metabolism. Mouse 1A1 had activity 40 times higher than any human, rabbit, or rodent P450s, indicating the potential pitfalls of extrapolating P450 activity across species. Metabolism of the 7, 8‐diol resulted in six metabolites (four tetrols and two triols). In the lymphoblastoid cells, human 1A1 was shown to be 4.2 times more active than 1A2 for 7, 8‐diol metabolism. Among human P450s expressed from vaccinia virus, 1A2, 2E1, and 2C9 gave the highest activity, and 2C8 and 3A4 showed moderate activity for 7, 8‐diol metabolism to the diol epoxides. Again, mouse 1A1 was much more active than any other P450. These studies, in which we determined the capacity of individual P450 in the metabolism and activation of B[a]P and 7, 8‐diol, may thus lead to a better understanding of how P450s control the detoxification and activation of polycyclic aromatic hydrocarbons. © 1994 Wiley‐Liss, Inc.
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人肝微粒体细胞色素 P-450 酶参与鼠伤寒沙门氏菌 TA 1535/pSK1002 中 Umu 基因反应检测到的原致癌物的生物激活。
影响因子：
11.2
作者：
Shimada,T;Iwasaki,M;Martin,MV;Guengerich,FP
通讯作者：
Guengerich,FP
各种形式的细胞色素 P450 对人肝微粒体苯并[a]芘代谢的相对贡献。
影响因子：
4.7
作者：
Hall,M;Forrester,LM;Parker,DK;Grover,PL;Wolf,CR
通讯作者：
Wolf,CR
DOI：
10.1073/pnas.87.12.4790
发表时间：
1990-06-01
影响因子：
11.1
作者：
AOYAMA, T;YAMANO, S;GONZALEZ, FJ
通讯作者：
GONZALEZ, FJ
影响因子：
3.8
作者：
Yoshihara, S;Makishima, M;Ohta, S
通讯作者：
Ohta, S
影响因子：
11.2
作者：
T. Shimada;Martha V. Martin;D. Pruess-Schwartz;L. Marnett;F. Guengerich
通讯作者：
T. Shimada;Martha V. Martin;D. Pruess-Schwartz;L. Marnett;F. Guengerich