Hydroxy metabolites of polychlorinated biphenyls (OH-PCBs) exhibit inhibitory effects on UDP-glucuronosyltransferases (UGTs)

Hydroxy metabolites of polychlorinated biphenyls (OH-PCBs) are important substance basis for the toxicity of PCBs. This study aims to investigate the inhibition of OH-PCBs on the activity of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of PCBs from a new perspective. In vitro human recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4 MU) was used as the probe reaction. The number of chlorine atom can affect the inhibition potential of OH-PCBs towards different isoforms of UGTs, and complex structure-activity relationship was found for the inhibition of OH-PCBs on the activities of UGT isoforms. For the inhibition kinetic determination, 2'-OH-PCB106 and 4'-OH-PCB106 were selected as the representative OH-PCBs, and UGT1A1, 1A7, and 267 were chosen as the representative UGT isoforms. Competitive inhibition of 2'-OH-PCB106 and 4'-OH-PCB106 on the activities of UGT1A1, UGT1A7, and UGT2B7 was found. For 2'-OH-PCB106, the inhibition kinetic parameters (KO were calculated to be 0.4 mu M for UGT1A1, 1.3 mu M for UGT1A7, and 2.7 mu M for UGT2B7, respectively. For 4'-OH-PCB106, K-i values were calculated to be 0.7 mu M for UGT1A1, 6.8 mu M for UGT1A7, and 4.8 mu M for UGT2B7, respectively. In silico docking method was utilized to elucidate the inhibition difference of UGT1A1 by four OH-PCBs with similar structures (4'-OH-PCB9, 4'-OH-PCB26, 4'-OH-PCB112 and 4'-OH-PCB165). In conclusion, these data will be helpful for understanding the toxicity mechanisms of PCBs from a view of metabolic interference. (C) 2018 Elsevier Ltd. All rights reserved.