Inhibition of UDP-glucuronosyltransferases (UGTs) by polycyclic aromatic hydrocarbons (PAHs) and hydroxy-PAHs (OH-PAHs)

• Published in: Environmental pollution (1987) 2020-08, Vol.263 (Pt B), p.114521-114521, Article 114521
• Main Authors: Yang, Qiaoyun, Bai, Yu, Qin, Guo-Qiang, Jia, Ruo-Yong, Zhu, Weihua, Zhang, Dafang, Fang, Zhong-Ze
• Format: Article
• Language: English
• Subjects: Hydroxy-polycyclic aromatic hydrocarbons (OH-PAHs); Inhibition kinetics; Molecular docking; Polycyclic aromatic hydrocarbons (PAHs); UDP-glucuronosyltransferases (UGTs)
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2020.114521

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. [Display omitted] •OH-PAHs showed stronger inhibitory ability than PAHs on UGTs.•1-HOPYR showed the strongest inhibitory ability on UGTs.•UGT1A6 and UGT1A9 are most vulnerable UGT isoforms to PAHs and OH-PAHs.•High possibility existed for the inhibition of OH-PAHs towards UGT1A6 and UGT1A9.•Hydrophobic interaction contributed to the inhibition behavior.