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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
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
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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
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。
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