Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin, 300070, China; Tianjin Center for International Collaborative Research in Environment, Nutrition and Public Health, Tianjin, China.
Chemosphere. 2020 Jan;238:124645. doi: 10.1016/j.chemosphere.2019.124645. Epub 2019 Aug 24.
Bromophenols (BPs) are important organic compounds which have become dominant pollutants during these years. Our present study investigated the potential inhibition behaviour of BPs on the activity of one of the most important phase II drug-metabolizing enzymes (DMEs), UDP-glucuronosyltransferases (UGTs). Recombinant UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was utilized as the probe reaction. 100 μM of BPs was utilized as the inhibition screening concentrations, and the complete inhibition profile of UGT isoforms by BPs was obtained. UGT1A7 was the most vulnerable UGT isoform towards BPs. Some structure-activity relationship for the inhibition of UGTs by BPs was found, and this relationship can be furtherly explained by the hydrophobic contacts of BPs with the activity cavity of UGTs using in silico docking method. The inhibition kinetics determination showed that the inhibition kinetic parameter K value was calculated to be 2.85, 3.99 and 31.00 μM for the inhibition of UGT1A3, UGT1A7, and UGT2B7 by representative BPs, 2,4,6-TBP. Combined with in vivo exposure concentration of 2,4,6-TBP, in vitro-in vivo extrapolation (IVIVE) was employed to demonstrate the moderate possibility for the inhibition of UGT1A3 and UGT1A7 by 2,4,6-TBP. In conclusion, our study gave the full description towards the inhibition of BPs towards UGT isoforms, which will provide a new perspective for elucidating the toxicity mechanism of bromophenols (BPs).
溴酚类（BPs）是重要的有机化合物，近年来已成为主要的污染物。本研究探讨了 BPs 对一种最重要的 II 相药物代谢酶（DMEs），即尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）活性的潜在抑制作用。利用重组 UDP-葡萄糖醛酸基转移酶（UGTs）催化的 4-甲基伞形酮（4-MU）的葡萄糖醛酸化作为探针反应。使用 100µM 的 BPs 作为抑制筛选浓度，获得了 BPs 对 UGT 同工型的完全抑制谱。UGT1A7 是对 BPs 最敏感的 UGT 同工型。发现了 BPs 抑制 UGTs 的一些构效关系，并且可以通过使用计算对接方法研究 BPs 与 UGTs 的活性腔的疏水接触来进一步解释这种关系。抑制动力学测定表明，代表 BPs 之一的 2,4,6-TBP 对 UGT1A3、UGT1A7 和 UGT2B7 的抑制动力学参数 K 值分别计算为 2.85、3.99 和 31.00µM。结合 2,4,6-TBP 的体内暴露浓度，采用体外-体内外推法（IVIVE）来证明 2,4,6-TBP 中度可能抑制 UGT1A3 和 UGT1A7。总之，本研究全面描述了 BPs 对 UGT 同工型的抑制作用，为阐明溴酚类（BPs）的毒性机制提供了新的视角。
