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 Apr;197:7-13. doi: 10.1016/j.chemosphere.2018.01.010. Epub 2018 Jan 5.
Phthalate monoesters are important metabolites of phthalate esters (PAEs) which have been extensively utilized in industry. This study aims to investigate the inhibition of phthalate monoesters on the activity of various isoforms of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of environmental endocrine disruptors from the new perspectives. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to evaluate 8 kinds of phthalate monoesters on 11 sorts of main human UGT isoforms. 100 μM phthalate monoesters exhibited negligible inhibition towards the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A8, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17. The activity of UGT1A7 was strongly inhibited by monoethylhexyl phthalate (MEHP), but slightly inhibited by all the other phthalate monoesters. UGT1A9 was broadly inhibited by monobenzyl phthalate (MBZP), monocyclohexyl phthalate (MCHP), MEHP, monohexyl phthalate (MHP) and monooctyl phthalate (MOP), respectively. MEHP exhibited competitive inhibition towards UGT1A7, and MBZP, MCHP, MEHP, MHP and MOP showed competitive inhibition towards UGT1A9. The inhibition kinetic parameters (K) were calculated to be 11.25 μM for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 μM for MBZP-UGT1A9, MCHP-UGT1A9, MEHP-UGT1A9, MHP-UGT1A9, MOP-UGT1A9, respectively. Molecular docking indicated that both hydrogen bonds formation and hydrophobic interactions significantly contributed to the interaction between phthalate monoesters and UGT isoforms. All these information will be beneficial for understanding the adverse effects of PAEs.
邻苯二甲酸单酯是邻苯二甲酸酯（PAEs）的重要代谢物，广泛应用于工业领域。本研究旨在探讨邻苯二甲酸单酯对各种 UDP-葡萄糖醛酸转移酶（UGTs）同工型活性的抑制作用，试图从新的角度阐明环境内分泌干扰物的毒性机制。采用体外重组 UGTs 催化 4-甲基伞形酮（4-MU）的葡萄糖醛酸化反应，评估 8 种邻苯二甲酸单酯对 11 种主要人 UGT 同工型的影响。100μM 邻苯二甲酸单酯对 UGT1A1、UGT1A3、UGT1A6、UGT1A8、UGT1A10、UGT2B4、UGT2B7、UGT2B15 和 UGT2B17 的活性几乎没有抑制作用。单乙基己基邻苯二甲酸酯（MEHP）强烈抑制 UGT1A7 的活性，而其他邻苯二甲酸单酯则轻微抑制其活性。单苄基邻苯二甲酸酯（MBZP）、单环己基邻苯二甲酸酯（MCHP）、MEHP、单己基邻苯二甲酸酯（MHP）和单辛基邻苯二甲酸酯（MOP）分别广泛抑制 UGT1A9 的活性。MEHP 对 UGT1A7 表现出竞争性抑制作用，而 MBZP、MCHP、MEHP、MHP 和 MOP 对 UGT1A9 表现出竞争性抑制作用。抑制动力学参数（K）计算值分别为 11.25μM 用于 MEHP-UGT1A7，以及 2.13、0.09、1.17、7.47、0.16μM 用于 MBZP-UGT1A9、MCHP-UGT1A9、MEHP-UGT1A9、MHP-UGT1A9、MOP-UGT1A9。分子对接表明，氢键形成和疏水相互作用都显著促进了邻苯二甲酸单酯与 UGT 同工型之间的相互作用。这些信息将有助于理解 PAEs 的不良影响。
