title: The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3).
abstract: 1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0 μM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.
authors.affiliation: a Department of Thyroid and Neck Tumor , Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy , Tianjin , China.|b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chen
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Zuo
authors.initials: Z
authors.lastname: Du
authors.affiliation: c Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China , and.
authors.forename: Chun-Ze
authors.initials: CZ
authors.lastname: Zhang
authors.affiliation: c Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China , and.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Zhang
authors.affiliation: d Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM) , Jinzhou , Liaoning , China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: d Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM) , Jinzhou , Liaoning , China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Sun
authors.affiliation: d Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM) , Jinzhou , Liaoning , China.
authors.forename: Zhi-Tu
authors.initials: ZT
authors.lastname: Zhu
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Yong-Zhe
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Ze-Wei
authors.initials: ZW
authors.lastname: Zhao
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Fu
authors.affiliation: a Department of Thyroid and Neck Tumor , Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy , Tianjin , China.
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Gu
authors.affiliation: a Department of Thyroid and Neck Tumor , Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy , Tianjin , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: b Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006923:Hymecromone / Q000378:metabolism; D062105:Molecular Docking Simulation; D013974:Thyroxine / Q000737:chemistry / Q000494:pharmacology*; D014284:Triiodothyronine / Q000737:chemistry / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
chemical_list: D004791:Enzyme Inhibitors; D014453:Glucuronosyltransferase; D006923:Hymecromone; D013974:Thyroxine; D014284:Triiodothyronine; D000099148:UGT1A1 Enzyme; C122075:UDP-glucuronosyltransferase, UGT1A3; C491474:UGT2B7 protein, human; C524630:UGT1A7 protein, human
keywords: Enzyme inhibition; UDP-glucuronosyltransferases; thyroxine; triiodothyronine