Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
Chemosphere. 2018 Sep;206:9-16. doi: 10.1016/j.chemosphere.2018.04.148. Epub 2018 Apr 24.
Chlorophenols (CPs) are important pollutants extensively utilized in industry, agriculture and forestry. The present study aims to determine the inhibition of CPs on the activity of the important phase II drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). 100 μM of fourteen CPs were used for preliminary screening using in vitro incubation. Furthermore, half inhibition concentration (IC) and inhibition kinetics were determined for CPs with significant inhibition towards UGT isoforms. In silico docking was used to explain the inhibition difference among CPs. Multiple UGT isoforms were inhibited by CPs. In silico docking showed that higher free binding energy due to hydrophobic interactions of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) with UGT1A9 contributed to stronger inhibition potential of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) towards UGT1A9 than 4-CP. Pentachlorophenol (PCP) was chosen as the representative CPs to determine the IC value towards UGT1A6, UGT1A9 and UGT2B7. IC was calculated to be 0.33 μM, 0.24 μM and 31.35 μM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. PCP was demonstrated to show competitive inhibition towards UGT1A6, UGT1A9 and UGT2B7, and the inhibition kinetic parameters (Ki) was calculated to be 0.18 μM, 0.01 μM and 5.37 μM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. All these information will be beneficial for elucidating the risk of CPs exposure from a new perspective.
氯酚类化合物（CPs）是工业、农业和林业中广泛应用的重要污染物。本研究旨在确定 CPs 对重要的Ⅱ相药物代谢酶（DMEs）尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）活性的抑制作用。使用体外孵育对 14 种 CPs 的 100μM 进行了初步筛选。此外，对具有显著抑制 UGT 同工型的 CPs 进行了半抑制浓度（IC）和抑制动力学测定。使用计算机对接来解释 CPs 之间抑制差异的原因。多种 UGT 同工型被 CPs 抑制。计算机对接显示，由于 2,4-二氯苯酚（2.4-DCP）或 4-氯-3-甲基苯酚（4C3MP）与 UGT1A9 之间的疏水相互作用导致更高的自由结合能，导致 2,4-二氯苯酚（2.4-DCP）或 4-氯-3-甲基苯酚（4C3MP）对 UGT1A9 的抑制潜力强于 4-CP。五氯苯酚（PCP）被选为代表 CPs 来确定其对 UGT1A6、UGT1A9 和 UGT2B7 的 IC 值。对于 PCP 对 UGT1A6、UGT1A9 和 UGT2B7 的抑制，IC 计算值分别为 0.33μM、0.24μM 和 31.35μM。PCP 被证明对 UGT1A6、UGT1A9 和 UGT2B7 表现出竞争性抑制，抑制动力学参数（Ki）计算值分别为 0.18μM、0.01μM 和 5.37μM，用于 PCP 对 UGT1A6、UGT1A9 和 UGT2B7 的抑制。所有这些信息都将有助于从新的角度阐明 CPs 暴露的风险。
