期刊
CHEMOSPHERE
卷 185, 期 -, 页码 983-990出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2017.07.105
关键词
Phthalate esters; Uridine diphosphate; glucuronosyltransferases; Kinetic parameters
资金
- project for the National Key Research and Development Program [2016YFC0903100, 2016YFC0903102]
- National Natural Science Foundation of China [81602826, 81672961]
- individualized diagnosis and treatment of colorectal cancer [LNCCC-B05-2015]
- Foundation of Committee on Science and Technology of Tianjin [15JCYBJC54700]
- China Postdoctoral Science Foundation [2016M590210]
- Tianjin Health Bureau Science Foundation [16KG154]
- Tianjin Project of Thousand Youth Talents
- 13th five year plan and TMU talent project [11601501/2016KJ0313]
Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The K1 values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 JAM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBPUGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs. (C) 2017 Elsevier Ltd. All rights reserved.
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