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 using in vitro recombinant 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 vivo extrapolation (IVIVE) showed that high in vivo inhibition 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.

中文翻译：

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多环芳烃（PAH）和羟基-PAH（OH-PAH）抑制UDP-葡萄糖醛酸转移酶（UGT）。

多环芳烃（PAHs）是不可避免的副产物燃烧引起的普遍存在的环境污染物之一。尽管数十年来一直在研究对人类的不良健康影响，但PAH及其羟基化代谢产物（OH-PAHs）对UDP-葡萄糖醛酸糖基转移酶（UGT）的影响仍不清楚。这项研究旨在调查的结构依赖14 PAHs和OH-PAHs对UGTs的7个亚型的活性的抑制作用，使用体外重组UGTs催化的4-甲基伞形酮（4-MU）的葡萄糖醛酸化作用作为探针反应。PAHs和OH-PAHs对不同程度的不同UGT亚型表现出抑制作用。为了确定抑制动力学，使用1-HONAP，4-HOPHE，9-HOPHE和1-HOPYR作为代表化合物，UGT1A6 选择了UGT1A9和UGT2B7作为三种代表性的UGT亚型。4-HOPHE，9-HOPHE和1-HOPYR对以上三种UGT亚型的抑制作用相同：UGT1A9> UGT1A6> UGT2B; 对于1-HONAP，即UGT1A6> UGT1A9> UGT2B。利用分子对接方法寻找UGT1A9和UGT2B7与1-HONAP和1-HOPYR结合的活性腔。氢键和疏水接触是它们相互作用的主要贡献者。体外-体内外推法（IVIVE）显示，存在较高的体内抑制可能性，以抑制UGT上的OH-PAHs。所有结果为解释PAHs和OH-PAHs的毒性提供了新颖的观点。对于1-HONAP，即UGT1A6> UGT1A9> UGT2B。利用分子对接方法寻找UGT1A9和UGT2B7与1-HONAP和1-HOPYR结合的活性腔。氢键和疏水接触是它们相互作用的主要贡献者。体外-体内外推法（IVIVE）显示，存在较高的体内抑制可能性，以抑制UGT上的OH-PAHs。所有结果为解释PAHs和OH-PAHs的毒性提供了新颖的观点。对于1-HONAP，即UGT1A6> UGT1A9> UGT2B。利用分子对接方法寻找UGT1A9和UGT2B7与1-HONAP和1-HOPYR结合的活性腔。氢键和疏水接触是它们相互作用的主要贡献者。体外-体内外推法（IVIVE）显示，存在较高的体内抑制可能性，以抑制UGT上的OH-PAHs。所有结果为解释PAHs和OH-PAHs的毒性提供了新颖的观点。体外-体内外推法（IVIVE）显示，存在较高的体内抑制可能性，以抑制UGT上的OH-PAHs。所有结果为解释PAHs和OH-PAHs的毒性提供了新颖的观点。体外-体内外推法（IVIVE）显示，存在较高的体内抑制可能性，以抑制UGT上的OH-PAHs。所有结果为解释PAHs和OH-PAHs的毒性提供了新颖的观点。