期刊
CHEMOSPHERE
卷 212, 期 -, 页码 513-522出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2018.08.040
关键词
Hydroxy metabolites of polychlorinated; biphenyls (OH-PCBs); UDP-Glucuronosyltransferases (UGTs); Toxicity
资金
- project for the National Key Research and Development Program [2016YFC0903100, 2016YFC0903102]
- National Natural Science Foundation of China [81602850]
- Foundation of Committee on Science and Technology of Tianjin [15JCYBJC54700]
- China Postdoctoral Science Foundation [2016M590210, 20177100164]
- Tianjin Health Bureau Science Foundation Key Project [16KG154]
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences [KF2017]
- Postgraduate Innovation Fund of '13th Five Year comprehensive investment', Tianjin Medical University [YJSCX201816]
- Natural Science Foundation of Liaoning Province [L2015317]
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.
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