Metabolic activation of polycyclic aromatic hydrocarbons and aryl and heterocyclic amines by human cytochromes P450 2A13 and 2A6.
Metabolic activation of polycyclic aromatic hydrocarbons and aryl and heterocyclic amines by human cytochromes P450 2A13 and 2A6.
复制标题
DOI：
10.1021/tx3004906
复制
发表时间：
2013-04-15
影响因子：
4.1
通讯作者：
Guengerich FP
中科院分区：
文献类型：
--
作者：
Shimada T;Murayama N;Yamazaki H;Tanaka K;Takenaka S;Komori M;Kim D;Guengerich FP
人们发现人细胞色素 P450 (P450) 2A13 与多种多环芳烃 (PAH) 相互作用，产生 I 型结合光谱，包括苊、苊、苯并[c]菲、荧蒽、荧蒽-2,3-二醇和 1-硝基芘。 P450 2A6 还与苊和苊相互作用，但不与荧蒽、荧蒽-2,3-二醇或 1-硝基芘相互作用。众所周知，P450 1B1 可以氧化许多致癌的 PAH，我们发现几种 PAH（即 7,12-二甲基苯并[a]蒽、7,12-二甲基苯并[a]蒽-5,6-二醇、苯并[c]菲、荧蒽、荧蒽-2,3-二醇、5-甲基屈、 苯并[a]芘-4,5-二醇、苯并[a]芘-7,8-二醇、1-硝基芘、2-氨基蒽、2-氨基芴和2-乙酰氨基芴）与P450 1B1相互作用，产生反向I型结合光谱。在鼠伤寒沙门氏菌 NM2009 中检查了 PAH 和芳基胺和杂环胺代谢激活基因毒性产物的情况，我们发现 P450 2A13 和 2A6（以及 P450 1B1）能够激活其中几种致癌物质。前两种酶在催化 2-氨基芴和 2-氨基蒽活化中特别活跃，分子对接模拟在 P450 2A13 和 2A6 活性位点的结合方面支持了这些致癌物的结果。这些结果表明，P450 2A 酶以及包括 P450 1B1 在内的 P450 家族 1 酶是参与激活 PAH、芳基胺和杂环胺以及烟草相关亚硝胺的主要酶。
Human cytochrome P450 (P450) 2A13 was found to interact with several polycyclic aromatic hydrocarbons (PAHs) to produce Type I binding spectra, including acenaphthene, acenaphthylene, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, and 1-nitropyrene. P450 2A6 also interacted with acenaphthene and acenaphthylene, but not with fluoranthene, fluoranthene-2,3-diol, or 1-nitropyrene. P450 1B1 is well known to oxidize many carcinogenic PAHs, and we found that several PAHs (i.e., 7,12-dimethylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene-5,6-diol, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, 5-methylchrysene, benz[a]pyrene-4,5-diol, benzo[a]pyrene-7,8-diol, 1-nitropyrene, 2-aminoanthracene, 2-aminofluorene, and 2-acetylaminofluorene) interacted with P450 1B1, producing Reverse Type I binding spectra. Metabolic activation of PAHs and aryl- and heterocyclic amines to genotoxic products was examined in Salmonella typhimurium NM2009, and we found that P450 2A13 and 2A6 (as well as P450 1B1) were able to activate several of these procarcinogens. The former two enzymes were particularly active in catalyzing 2-aminofluorene and 2-aminoanthracene activation, and molecular docking simulations supported the results with these procarcinogens, in terms of binding in the active sites of P450 2A13 and 2A6. These results suggest that P450 2A enzymes, as well as P450 Family 1 enzymes including P450 1B1, are major enzymes involved in activating PAHs and aryl- and heterocyclic amines, as well as tobacco-related nitrosamines.
登录
查看更多内容
影响因子：
3.2
作者：
Chen, YS;Ho, CC;Chung, JG
通讯作者：
Chung, JG
影响因子：
4.1
作者：
Jalas, JR;Hecht, SS
通讯作者：
Hecht, SS
影响因子：
4.8
作者：
Kim, D;Wu, ZL;Guengerich, FP
通讯作者：
Guengerich, FP
影响因子：
3.9
作者：
Bao, ZP;He, XY;Hong, JY
通讯作者：
Hong, JY
影响因子：
4.7
作者：
BUSBY, WF;GOLDMAN, ME;WOGAN, GN
通讯作者：
WOGAN, GN