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 300070, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin 300070, China.
Department of Surgery, Peking University Third Hospital, Beijing, China.
Environ Pollut. 2019 Nov;254(Pt B):113093. doi: 10.1016/j.envpol.2019.113093. Epub 2019 Aug 21.
Per- and polyfluoroalkyl substances (PFASs) are a large group of chemicals and can be detected in environmental and human samples all over the world. Toxicity of existing and emerging PFASs will be a long-term source of concern. This study aimed to investigate structure-dependent inhibitory effects of 14 PFASs towards the activity of 11 UDP-glucuronosyltransferase (UGT) isoforms. In vitro UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to determine the inhibition of PFASs towards different UGT isoforms. All the PFASs showed <75% of inhibition or stimulation effects on UGT1A3, UGT1A7, UGT1A9, UGT2B4, UGT2B7 and UGT2B17. However, PFASs showed broad inhibition on the activity of UGT1A1 and UGT1A8. The activity of UGT1A1 was inhibited by 98.8%, 98%, 79.9%, 77.1%, and 76.9% at 100 μmoL/L of perfluorodecanoic acid (PFDA), perfluorooctanesulfonic acid potassium salt (PFOS), perfluorotetradecanoic acid (PFTA), perfluorooctanoic acid (PFOA) and perfluorododecanoic acid (PFDoA), respectively. UGT1A8 was inhibited by 97.6%, 94.8%, 86.3%, 83.4% and 77.1% by PFDA, PFTA, perfluorooctadecanoic acid (PFOcDA), PFDoA and PFOS, respectively. Additionally, PFDA significantly inhibited UGT1A6 and UGT1A10 by 96.8% and 91.6%, respectively. PFDoA inhibited the activity of UGT2B15 by 88.2%. PFDA and PFOS exhibited competitive inhibition towards UGT1A1, and PFDA and PFTA showed competitive inhibition towards UGT1A8. The inhibition kinetic parameter (K) were 3.15, 1.73, 13.15 and 20.21 μmoL/L for PFDA-1A1, PFOS-1A1, PFDA-1A8 and PFTA-1A8, respectively. The values were calculated to be 0.3 μmoL/L and 1.3 μmoL/L for the in vivo inhibition of PFDA towards UGT1A1-and UGT1A8-catalyzed metabolism of substances, and 0.2 μmoL/L and 2.0 μmoL/L for the inhibition of PFOS towards UGT1A1 and the inhibition of PFTA towards UGT1A8, respectively. Molecular docking indicated that hydrogen bonds and hydrophobic interactions contributed to the interaction between PFASs and UGT isoforms. In conclusion, exposure to PFASs might inhibit the activity of UGTs to disturb metabolism of endogenous compounds and xenobiotics. The structure-related effects of PFASs on UGTs would be very important for risk assessment of PFASs.
全氟和多氟烷基物质（PFASs）是一大类化学物质，在世界各地的环境和人类样本中都能检测到。现有和新兴 PFASs 的毒性将是一个长期关注的问题。本研究旨在研究 14 种 PFASs 对 11 种 UDP-葡糖醛酸基转移酶（UGT）同工酶活性的结构依赖性抑制作用。采用体外 UGTs 催化的 4-甲基伞形酮（4-MU）葡糖醛酸化来确定 PFASs 对不同 UGT 同工酶的抑制作用。所有 PFASs 对 UGT1A3、UGT1A7、UGT1A9、UGT2B4、UGT2B7 和 UGT2B17 的抑制作用均<75%。然而，PFASs 对 UGT1A1 和 UGT1A8 的活性表现出广泛的抑制作用。在 100 μmoL/L 全氟癸酸（PFDA）、全氟辛烷磺酸钾盐（PFOS）、全氟十四烷酸（PFTA）、全氟辛酸（PFOA）和全氟十二烷酸（PFDoA）作用下，UGT1A1 的活性分别被抑制 98.8%、98%、79.9%、77.1%和 76.9%。UGT1A8 被 PFDA、PFTA、全氟十八烷酸（PFOcDA）、PFDoA 和 PFOS 分别抑制 97.6%、94.8%、86.3%、83.4%和 77.1%。此外，PFDA 对 UGT1A6 和 UGT1A10 的抑制作用分别为 96.8%和 91.6%。PFDoA 对 UGT2B15 的活性抑制率为 88.2%。PFDA 和 PFOS 对 UGT1A1 表现出竞争性抑制，PFDA 和 PFTA 对 UGT1A8 表现出竞争性抑制。抑制动力学参数（K）分别为 3.15、1.73、13.15 和 20.21 μmoL/L，用于 PFDA-1A1、PFOS-1A1、PFDA-1A8 和 PFTA-1A8。PFDA 对 UGT1A1 和 UGT1A8 催化的代谢物的体内抑制的计算值分别为 0.3 μmoL/L 和 1.3 μmoL/L，PFOS 对 UGT1A1 的抑制和 PFTA 对 UGT1A8 的抑制的计算值分别为 0.2 μmoL/L 和 2.0 μmoL/L。分子对接表明氢键和疏水相互作用有助于 PFASs 与 UGT 同工酶的相互作用。综上所述，接触 PFASs 可能会抑制 UGTs 的活性，从而干扰内源性化合物和外源性化合物的代谢。PFASs 对 UGTs 的结构相关影响对于 PFASs 的风险评估非常重要。
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