Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species
| Autor: | Zhi-Wei Fu, Wen-Xi Dang, Zhihua Pang, Qing Zhang, Jia-Jia Wang, Wenting Li, Yi-Xuan Li, Nai-Rong Liu, Kai Yang, Ruo-Yong Jia, Zhong-Ze Fang, Zhu-Hua Yao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Environmental Engineering
010504 meteorology & atmospheric sciences Swine 010501 environmental sciences 01 natural sciences Dogs Cytochrome P-450 Enzyme System Environmental Chemistry Animals Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans Animal species Waste Management and Disposal Inhibitory effect Liver microsomes 0105 earth and related environmental sciences Human liver biology CYP3A4 Chemistry Substrate (chemistry) Pollution Enzyme assay Rats Biochemistry biology.protein Microsomes Liver Human cytochrome Chlorophenols |
| Zdroj: | The Science of the total environment. 724 |
| ISSN: | 1879-1026 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect