Journal
CHEMOSPHERE
Volume 197, Issue -, Pages 7-13Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2018.01.010
Keywords
Phthalate esters (PAEs); Phthalate monoesters; UDP-glucuronosyltransferases (UGTs); Enzyme inhibition
Categories
Funding
- project for the National Key Research and Development Program [2016YFC0903100, 2016YFC0903102]
- 13th five year plan and TMU talent project [11601501/2016KJ0313]
- Foundation of Committee on Science and Technology of Tianjin [15JCYBJC54700, 14JCQNJC11300]
- China Postdoctoral Science Foundation [2016M590210, 2017T100164]
- Tianjin Health Bureau Science Foundation Key Project [16KG154]
- Tianjin Project of Thousand Youth Talents
- Key Laboratory Open Project Fund from State Key Laboratory of Environment Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences [KF2017-02]
- National Natural Science Fund [81602850]
- individualized diagnosis and treatment of colorectal cancer [LNCCC-B05-2015]
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Phthalate monoesters are important metabolites of phthalate esters (PAEs) which have been extensively utilized in industry. This study aims to investigate the inhibition of phthalate monoesters on the activity of various isoforms of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of environmental endocrine disruptors from the new perspectives. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to evaluate 8 kinds of phthalate monoesters on 11 sorts of main human UGT isoforms.100 mu M phthalate monoesters exhibited negligible inhibition towards the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A8, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17. The activity of UGT1A7 was strongly inhibited by monoethylhexyl phthalate (MEHP), but slightly inhibited by all the other phthalate monoesters. UGT1A9 was broadly inhibited by monobenzyl phthalate (MBZP), monocyclohexyl phthalate (MCHP), MEHP, monohexyl phthalate (MHP) and monooctyl phthalate (MOP), respectively. MEHP exhibited competitive inhibition towards UGT1A7, and MBZP, MCHP, MEHP, MHP and MOP showed competitive inhibition towards UGT1A9. The inhibition kinetic parameters (K-i) were calculated to be 11.25 mu M for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 mu M for MBZP-UGT1A9, MCHP-UGT1A9, MEHP-UGT1A9, MHP-UGT1A9, MOP-UGT1A9, respectively. Molecular docking indicated that both hydrogen bonds formation and hydrophobic interactions significantly contributed to the interaction between phthalate monoesters and UGT isoforms. All these information will be beneficial for understanding the adverse effects of PAEs. (C) 2018 Elsevier Ltd. All rights reserved.
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