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Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters.
Du, Zuo; Cao, Yun-Feng; Li, Sai-Nan; Hu, Cui-Min; Fu, Zhi-Wei; Huang, Chun-Ting; Sun, Xiao-Yu; Liu, Yong-Zhe; Yang, Kun; Fang, Zhong-Ze.
Afiliación
  • Du Z; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • Cao YF; Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
  • Li SN; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • Hu CM; Tianjin Life Science Research Center, Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • Fu ZW; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • Huang CT; RSKT Biopharma Inc., Liaoning, China.
  • Sun XY; RSKT Biopharma Inc., Liaoning, China.
  • Liu YZ; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • Yang K; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China.
  • Fang ZZ; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, China. Electronic address: fangzhongze@tmu.edu.cn.
Chemosphere ; 197: 7-13, 2018 Apr.
Article en En | MEDLINE | ID: mdl-29328989
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácidos Ftálicos / Glucuronosiltransferasa Límite: Humans Idioma: En Revista: Chemosphere Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácidos Ftálicos / Glucuronosiltransferasa Límite: Humans Idioma: En Revista: Chemosphere Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido