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Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species.
Science of the Total Environment ( IF 8.2 ) Pub Date : 2020-03-28 , DOI: 10.1016/j.scitotenv.2020.138187
Nai-Rong Liu 1 , Kai Yang 2 , Wen-Ting Li 3 , Zhi-Hua Pang 3 , Qing Zhang 1 , Jia-Jia Wang 1 , Wen-Xi Dang 1 , Ruo-Yong Jia 2 , Zhi-Wei Fu 4 , Yi-Xuan Li 5 , Zhu-Hua Yao 3 , Zhong-Ze Fang 2
Affiliation  

Chlorophenols (CPs) are important pollutants detected frequently in the environment. This study intended to detect the inhibitory effects of fourteen CPs (2-CP, 3-CP, 4-CP, 4C2AP, 4C3MP, 2.4-DCP, 2.3.4-TCP, 2.4.5-TCP, 2.4.6-TCP, 3.4.5-TCP, 2.3.4.5-TECP, 2.3.4.6-TECP, 2.3.5.6-TECP and PCP) towards human liver cytochrome P450 3A4 (CYP3A4). Throughout the tests, testosterone was used as the probe substrate and CPs were used as inhibitors. A series of experiments (enzyme activity assays, preliminary screening tests, inhibition kinetics determination) were conducted to determine the inhibition of CPs towards human liver CYP3A4. CPs with the inhibitory effect >80% were selected for the inhibition evaluation in liver microsomes from different animal species (monkey, rat, dog, pig). The results showed that 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP inhibited the activities of CYP3A4 by 80.3%, 93.4%, 91.6%, respectively. Inhibition kinetics type were non-competitive and inhibition kinetics constant (Ki) values were 26.4 μM, 13.5 μM, and 8.8 μM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards human CYP3A4, respectively. Inhibition kinetics type was competitive and Ki value was 4.9 μM for the inhibition of 2.3.4-TCP towards CYP3A4 in Monkey liver microsomes (MyLMs). Inhibition kinetic types were non-competitive and Ki values were 8.1 μM and 28.7 μM for the inhibition of 3.4.5-TCP and 2.3.4.5-TECP towards CYP3A4 in MyLMs. Inhibition kinetic types were non-competitive and Ki values were 13.8 μM, 0.6 μM, and 6.1 μM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards CYP3A4 in Dog liver microsomes (DLMs), respectively. By comparing Ki values and inhibition kinetic types, the dog was the most suitable model to assess the inhibition of 2.3.4-TCP and 2.3.4.5-TECP towards CYP3A4, and monkey was the most suitable model to assess the inhibition of 3.4.5-TCP towards CYP3A4. In conclusion, our recent study on the inhibition of CPs towards CYP3A4 and species differences was important for further toxicological studies of CPs in human bodies.

中文翻译:

评价氯酚对人细胞色素P450 3A4的抑制作用以及不同物种之间的差异。

氯酚(CPs)是在环境中经常检测到的重要污染物。本研究旨在检测14种CP(2-CP,3-CP,4-CP,4C2AP,4C3MP,2.4-DCP,2.3.4-TCP,2.4.5-TCP,2.4.6-TCP, 3.4.5-TCP,2.3.4.5-TECP,2.3.4.6-TECP,2.3.5.6-TECP和PCP)对人肝细胞色素P450 3A4(CYP3A4)的影响。在整个测试过程中,睾丸激素用作探针底物,CP用作抑制剂。进行了一系列实验(酶活性测定,初步筛选试验,抑制动力学测定),以确定CPs对人肝CYP3A4的抑制作用。选择抑制作用> 80%的CPs对来自不同动物物种(猴子,大鼠,狗,猪)的肝微粒体进行抑制评估。结果显示为2.3.4-TCP,3.4.5-TCP和2.3.4。5-TECP分别抑制CYP3A4的活性达80.3%,93.4%,91.6%。抑制动力学类型是非竞争性的,抑制2.3.4-TCP,3.4.5-TCP和2.3.4.5-TECP对人CYP3A4的抑制动力学常数(Ki)值分别为26.4μM,13.5μM和8.8μM。 , 分别。抑制动力学类型具有竞争性,在猴肝微粒体(MyLMs)中对CYP3A4的2.3.4-TCP抑制作用的Ki值为4.9μM。抑制动力学类型是非竞争性的,在MyLMs中对CYP3A4的3.4.5-TCP和2.3.4.5-TECP的抑制作用的Ki值为8.1μM和28.7μM。抑制动力学类型是非竞争性的,对狗肝微粒体(DLMs)对CYP3A4的2.3.4-TCP,3.4.5-TCP和2.3.4.5-TECP的抑制作用,Ki值为13.8μM,0.6μM和6.1μM。 ), 分别。通过比较Ki值和抑制动力学类型,狗是评估2.3.4-TCP和2.3.4.5-TECP对CYP3A4抑制作用的最合适模型,而猴子是评估3.4.5抑制作用的最合适模型。 -TCP朝向CYP3A4。总而言之,我们最近对CPs对CYP3A4的抑制作用和物种差异的研究对于进一步对CPs进行人体毒理学研究非常重要。
更新日期:2020-03-28
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