title: New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases.
abstract: Wide utilization of phthalates-containing products results in the significant exposure of humans to these compounds. Many adverse effects of phthalates have been documented in rodent models, but their effects in humans exposed to these chemicals remain unclear until more mechanistic studies on phthalate toxicities can be carried out. To provide new insights to predict the potential adverse effects of phthalates in humans, the recent study investigated the inhibition of representative phthalates di-n-octyl ortho-phthalate (DNOP) and diphenyl phthalate (DPhP) towards the important xenobiotic and endobiotic-metabolizing UDP-glucuronosyltransferases (UGTs). An in vitro UGTs incubation system was employed to study the inhibition of DNOP and DPhP towards UGT isoforms. DPhP and DNOP weakly inhibited the activities of UGT1A1, UGT1A7, and UGT1A8. 100 µM of DNOP inhibited the activities of UGT1A3, UGT1A9, and UGT2B7 by 41.8% (p < 0.01), 45.6% (p < 0.01), and 48.8% (p < 0.01), respectively. 100 µM of DPhP inhibited the activity of UGT1A3, UGT1A6, and UGT1A9 by 81.8 (p < 0.001), 49.1% (p < 0.05), and 76.4% (p < 0.001), respectively. In silico analysis was used to explain the stronger inhibition of DPhP than DNOP towards UGT1A3 activity. Kinetics studies were carried our to determine mechanism of inhibition of UGT1A3 by DPhP. Both Dixon and Lineweaver-Burk plots showed the competitive inhibition of DPhP towards UGT1A3. The inhibition kinetic parameter (Ki) was calculated to be 0.89 µM. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1>[I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), these studies predicted in vivo drug-drug interaction might occur when the plasma concentration of DPhP was above 0.089 µM. Taken together, this study reveales the potential for adverse effects of phthalates DNOP and DPhP as a result of UGT inhibition.
authors.affiliation: First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, China.
authors.forename: Rui-Xue
authors.initials: RX
authors.lastname: Ran
authors.affiliation: Institute of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the First Affiliated Hospital of Liaoning Medical University, Dalian, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the Affiliated Zhongshan Hospital of Dalian University, Zhongshan, Dalian, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Huang
authors.affiliation: Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the First Affiliated Hospital of Liaoning Medical University, Dalian, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the Affiliated Zhongshan Hospital of Dalian University, Zhongshan, Dalian, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Fu
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, China.
authors.forename: Rong-Shan
authors.initials: RS
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yong-Zhe
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Sun
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, 300070, China. Electronic address: fangzhongze@tmu.edu.cn.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
mesh_terms: D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D010795:Phthalic Acids / Q000494:pharmacology*; D012306:Risk
chemical_list: D007527:Isoenzymes; D010795:Phthalic Acids; D014453:Glucuronosyltransferase
keywords: Di-n-octyl ortho-phthalate (DNOP); Diphenyl phthalate (DPhP); Phthalates; UDP-glucuronosyltransferases (UGTs)