2. Academic Validation
  3. Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters

Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters

  • Chemosphere. 2018 Apr:197:7-13. doi: 10.1016/j.chemosphere.2018.01.010.
Zuo Du 1,  Yun-Feng Cao 2,  Sai-Nan Li 1,  Cui-Min Hu 3,  Zhi-Wei Fu 1,  Chun-Ting Huang 4,  Xiao-Yu Sun 4,  Yong-Zhe Liu 1,  Kun Yang 1,  Zhong-Ze Fang 5
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • 2 Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
  • 3 Tianjin Life Science Research Center, Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 4 RSKT Biopharma Inc., Liaoning, China.
  • 5 Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China. Electronic address: fangzhongze@tmu.edu.cn.
PMID: 29328989 DOI: 10.1016/j.chemosphere.2018.01.010
Abstract

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 μM 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 (Ki) were calculated to be 11.25 μM for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 μM 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.

Keywords

Enzyme inhibition; Phthalate esters (PAEs); Phthalate monoesters; UDP-glucuronosyltransferases (UGTs).

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