Inhibition of UDP-glucuronosyltransferases (UGTs) by polycyclic aromatic hydrocarbons (PAHs) and hydroxy-PAHs (OH-PAHs)
Inhibition of UDP-glucuronosyltransferases (UGTs) by polycyclic aromatic hydrocarbons (PAHs) and hydroxy-PAHs (OH-PAHs)
复制标题
多环芳烃 (PAH) 和羟基多环芳烃 (OH-PAH) 对 UDP-葡萄糖醛酸基转移酶 (UGT) 的抑制作用
DOI：
10.1016/j.envpol.2020.114521
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发表时间：
2020
影响因子：
8.9
通讯作者：
Fang Zhong-Ze
中科院分区：
文献类型：
--
作者：
Yang Qiaoyun;Bai Yu;Qin Guo-Qiang;Jia Ruo-Yong;Zhu Weihua;Zhang Dafang;Fang Zhong-Ze
多环芳烃（PAHs）是一种普遍存在的环境污染物，是由不可避免的副产品燃烧引起的。尽管对人类健康的不良影响进行了数十年的研究，但多环芳烃及其羟基化代谢物（OH-PAHs）对udp -葡萄糖醛酸糖基转移酶（UGTs）的影响仍不清楚。本研究以体外重组UGTs催化4-甲基伞草酮（4-MU）糖醛酸化为探针反应，研究了14种PAHs和OH-PAHs对7种UGTs同工型活性的抑制作用。PAHs和OH-PAHs对不同的UGT亚型有不同程度的抑制作用。以1-HONAP、4-HOPHE、9-HOPHE和1-HOPYR为代表化合物进行抑制动力学测定，选择UGT1A6、UGT1A9和UGT2B7为UGT的三个代表性亚型。4-HOPHE、9-HOPHE和1-HOPYR对上述三种UGT亚型的抑制作用相同：UGT1A9>UGT1A6>UGT2B；对于1-HONAP，表示UGT1A6>UGT1A9>UGT2B。利用分子对接方法寻找UGT1A9和UGT2B7与1-HONAP和1-HOPYR结合的活性空腔。氢键和疏水接触是它们相互作用的主要因素。体外-体内外推（IVIVE）结果表明，OH-PAHs对UGTs的抑制存在较高的体内抑制可能性。这些结果为解释多环芳烃和OH-PAHs的毒性提供了一个新的观点。
Polycyclic aromatic hydrocarbons (PAHs) are known as one of the ubiquitous environmental pollutants caused by unavoidable combustion of by-products. Despite decades of research on adverse health effects towards humans, the effects of PAHs and their hydroxylated metabolites (OH-PAHs) on UDP-glucuronosyltransferases (UGTs) remain unclear. This study aimed to investigate inhibitory effects with structure-dependence of 14 PAHs and OH-PAHs towards the activity of 7 isoforms of UGTs usingin vitrorecombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) as the probe reaction. PAHs and OH-PAHs showed inhibitory effects towards different UGT isoforms with different extents. For inhibition kinetics determination, 1-HONAP, 4-HOPHE, 9-HOPHE, and 1-HOPYR were utilized as the representative compounds, and UGT1A6, UGT1A9 and UGT2B7 were chosen as the three representative UGT isoforms. The inhibitory effects of 4-HOPHE, 9-HOPHE and 1-HOPYR on three above UGT isoforms were the same: UGT1A9>UGT1A6>UGT2B; for 1-HONAP, that is UGT1A6>UGT1A9>UGT2B. Molecular docking methods were utilized to find the activity cavity of UGT1A9 and UGT2B7 binding with 1-HONAP and 1-HOPYR. Hydrogen bonds and hydrophobic contacts were mainly contributors to their interactions.In vitro-in vivoextrapolation (IVIVE) showed that highin vivoinhibition possibility exists for the inhibition of OH-PAHs on UGTs. All the results provide a novel viewpoint for an explanation of the toxicity of PAHs and OH-PAHs.