Different mechanisms for inhibition of human cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic inhibitors
Different mechanisms for inhibition of human cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic inhibitors
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DOI：
10.1021/tx600299p
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发表时间：
2007-03-01
影响因子：
4.1
通讯作者：
Guengerich, F. Peter
中科院分区：
文献类型：
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作者：
Shimada, Tsutomu;Murayama, Norie;Guengerich, F. Peter
我们先前已经表明，几种多环芳烃（PAH）强烈抑制其自身和由细胞色素P450（P450）1A 1、1A 2和1B 1催化的其它PAH代谢[Shimada，T.，和Guengerich，F. P.（2006）Chem. Res. Toxicol. 19，288-294]。在本研究中，我们研究了多环芳烃如何抑制这些P450酶使用7-乙氧基试卤灵O-脱乙基（EROD）作为模型反应的机制。首先，我们研究了合成的模型抑制剂1-（1-丙炔基）芘（1 PP）、1-乙炔基芘（1 EP）、2-乙炔基芘（2 EP）和4-（1-丙炔基）联苯（4Pbi）对P450 1A 1、1A 2和1B 1的抑制机制。1 PP和1 EP均以基于机制的方式抑制P450 1A 1，但1 PP和1 EP直接抑制P450 1B 1和1A 2。有趣的是，P450 1B 1使1 PP和1 EP失活为对P450 1B 1无抑制作用的产物。4Pbi是P450 1A 1和1B 1的机制性抑制剂，而2 EP直接抑制这些P450。所有四种抑制剂都直接抑制P450 1A 2。我们还发现，苯并[a]芘和其他七种PAH化合物测试抑制P450 1A 2的机制为基础的方式，但荧蒽直接抑制P450 1A 2。所检测的9种多环芳烃均为P450 1A 1和P450 1B 1的直接抑制剂。这些结果表明，不同的机制抑制P450 1A 1，1A 2，和1B 1的多环芳烃和相关化学品和P450酶和多环芳烃抑制剂之间的相互作用参与的酶的抑制差异。
We have previously shown that several polycyclic aromatic hydrocarbons (PAHs) strongly inhibit their own and other PAH metabolism catalyzed by cytochrome P450 (P450) 1A1, 1A2, and 1B1 [Shimada, T., and Guengerich, F. P. (2006) Chem. Res. Toxicol. 19, 288-294]. In the present study, we examined mechanisms of how PAHs inhibit these P450 enzymes by using 7-ethoxyresorufin O-deethylation (EROD) as a model reaction. First, we examined mechanisms of inhibition of P450 1A1, 1A2, and 1B1 by the synthetic model inhibitors 1-(1-propynyl)pyrene (1PP), 1-ethynylpyrene (1EP), 2-ethynylpyrene (2EP), and 4-(1-propynyl)biphenyl (4Pbi). Both 1PP and 1EP inhibited P450 1A1 in a mechanism-based manner, but P450 1B1 and 1A2 were directly inhibited by 1PP and 1EP. Interestingly, P450 1B1 inactivated 1PP and 1EP to products that were not inhibitory to P450 1B1. 4Pbi was a mechanism-based inhibitor of P450 1A1 and 1B1, but 2EP directly inhibited these P450s. All four of the inhibitors directly inhibited P450 1A2. We also found that benzo[a]pyrene and seven other PAH compounds tested inhibited P450 1A2 in a mechanism-based manner, but fluoranthene directly inhibited P450 1A2. All of the nine PAHs examined were direct inhibitors of P450 1A1 and P450 1B1. These results suggest different mechanisms of inhibition of P450 1A1, 1A2, and 1B1 by PAHs and related chemicals and that interactions between P450 enzymes and PAH inhibitors are involved in differences in inhibition of the enzymes.