New insights for the risk of bisphenol A: Inhibition of UDP-glucuronosyltransferases (UGTs) |
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Authors: | Hua-Mao Jiang Zhong-Ze Fang Yun-Feng Cao Cui-Min Hu Xiao-Yu Sun Mo Hong Ling Yang Guang-Bo Ge Yong Liu Yan-Yan Zhang Qiang Dong Ren-Jie Liu |
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Institution: | 1. Liaoning Medical University, Jinzhou, Liaoning, China;2. Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian 116023, China;3. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;4. Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;5. Department of Microbiology & Immunology, Georgetown University Medical Center, Washington DC, 20057, USA |
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Abstract: | Bisphenol A (BPA), the important endocrine-disrupting chemical (EDC), has been reported to be able to induce various toxicity. The present study aims to understand the toxicity behavior of bisphenol A through evaluating the inhibition profile of bisphenol A towards UDP-glucuronosyltransferase (UGT) isoforms. In vitro recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as probe reaction for all the tested UGT isoforms. The results showed that bisphenol A exerted stronger inhibition towards UGT2B isoforms than UGT1A isoforms. Furthermore, the inhibition kinetic type and parameters (Ki) were determined for the inhibition of bisphenol A towards UGT2B4, 2B7, 2B15, and 2B17. Bisphenol A exhibited the competitive inhibition towards UGT2B4, and noncompetitive inhibition towards UGT2B7, 2B15 and 2B17. The inhibition kinetic parameters (Ki) were calculated to be 1.1, 32.6, 5.6, and 19.9 μM for UGT2B4, 2B7, 2B15 and 2B17, respectively. In combination with the in vivo concentration of bisphenol A, the elevation of exposure dose was predicted to increase by 29.1%, 1%, 5.7%, and 1.6% for UGT2B4, 2B7, 2B15, and 2B17, indicating the high influence of bisphenol A towards the in vivo UGT2B isofroms-mediated metabolism of xenobiotics and endogenous substances. All these data provide the supporting information for deeper understanding of toxicology of bisphenol A. |
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Keywords: | Bisphenol A UDP-glucuronosyltransferase (UGT) Risk evaluation Recombinant enzymes |
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