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

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.