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

Chemosphere
Sai-Nan LiZhong-Ze Fang

Abstract

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 vitrohuman 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'OHPCB106 and 4'OHPCB106 were selected as the representative OH-PCBs, and UGT1A1, 1A7, and 2B7 were chosen as the representative UGT isoforms. Competitive inhibition of 2'OHPCB106 and 4'OHPCB106 on the activities of UGT1A1, UGT1A7, and UGT2B7 was found. For 2'OHPCB106, the inhibition kinetic parameters (Ki) were calculated to be 0.4 μM for UGT1A1, 1.3 μM for UGT1A7, and 2.7 μM for UGT2B7, respectively. For 4'OHPCB106, Ki values were calculated to be 0.7 μM for UGT1A1, 6.8 μM for UGT1A7, and 4.8 μM for UGT2B7, respectively. In silico docking met...Continue Reading

Citations

May 6, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yixuan LiChunze Zhang

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