title: The inhibition of UDP-glucuronosyltransferases (UGTs) by vitamin A.
abstract: 1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective. 2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 μM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (Ki) were calculated to be 31.1, 16.8, 2.2, and 11.6 μM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A. 3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.
authors.affiliation: a First Affiliated Hospital of Liaoning Medical University , Jinzhou , Liaoning , China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: b RSKT Biopharma Inc. , Liaoning , China.|c 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.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: d Institute of Integrative Medicine, Dalian Medical University , Dalian , China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.affiliation: e Department of Food Science and Technology , School of Life Sciences, Anqing Normal University , China.
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: f Tianjin Union Medical Center, Hongqiao District , Tianjin , China , and.
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: b RSKT Biopharma Inc. , Liaoning , China.|c 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: b RSKT Biopharma Inc. , Liaoning , China.|c 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.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Fu
authors.affiliation: b RSKT Biopharma Inc. , Liaoning , China.|c 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.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Huang
authors.affiliation: g Department of Toxicology , School of Public Health, Tianjin Medical University , Tianjin , China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: a First Affiliated Hospital of Liaoning Medical University , Jinzhou , Liaoning , China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Sun
mesh_terms: D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006923:Hymecromone; D007700:Kinetics; D014801:Vitamin A / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014801:Vitamin A; D006923:Hymecromone; D014453:Glucuronosyltransferase
keywords: Enzyme inhibition; UDP-glucuronosyltransferases (UGTs); vitamin A