title: Inhibition potential of UDP-glucuronosyltransferases (Ugts) 1A isoforms by the analogue of resveratrol, bakuchiol.
abstract: Bakuchiol is a promising anti-tumor candidate with resveratrol-like structure. The present study aims to evaluate the inhibition potential of bakuchiol towards UDP-glucuronosyltransferases (UGT) 1A isoforms. An in vitro incubation system using 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition capability of bakuchiol towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9 and 1A10. The glucuronidation of trifluoperazine (TFP) was employed as the probe reaction to determine bakuchiol's inhibition towards UGT1A4. At 1 microM and 10 microM of bakuchiol, no or weak inhibition was observed for all the tested UGT1A isoforms. At 100 microM of bakuchiol, the activity of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9 and 1A10 was inhibited by -46.2%, 74.7%, 17.8%, 98.7%, 70.4%, 99.2%, 75.8%, and 93.3%, respectively. Further inhibition kinetic behaviour was determined for UGT1A6, 1A8, and 1A10. Both Dixon plot and Lineweaver-Burk plot showed the noncompetitive inhibition of bakuchiol towards all these three UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 5.3, 1.8, and 92.6 microM for UGT1A6, 1A8, and 1A10, respectively. In combination with the in vivo exposure of bakuchiol, the high possibility of in vivo inhibition of UGT1A6 and 1A8 was predicted. However, relatively low possibility of in vivo inhibition towards UGT1A10 was predicted due to lower in vivo concentration of bakuchiol than its inhibition parameter (Ki). All these information will be helpful for the R&D of bakuchiol as a promising anti-tumor drug.
authors.affiliation: The Second Hospital of Dalian Medical University, Dalian, Liaoning, China. dongdegang12345678@163.com
authors.forename: De-Gang
authors.initials: DG
authors.lastname: Dong
authors.affiliation: Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors.forename: Shu-Lan
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: The Affiliated Hospital of Liaoning University of Chinese Traditional Medicine, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.affiliation: The Affiliated Hospital of Liaoning University of Chinese Traditional Medicine, Liaoning, China.
authors.forename: En-Mian
authors.initials: EM
authors.lastname: Guo
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.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
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.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D010636:Phenols / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
chemical_list: D004791:Enzyme Inhibitors; D014453:Glucuronosyltransferase; D007202:Indicators and Reagents; D007527:Isoenzymes; D010636:Phenols; D000077185:Resveratrol; D013267:Stilbenes; D000099148:UGT1A1 Enzyme; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; C012765:bakuchiol