title: Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin.
abstract: OBJECTIVE
  This study aimed to characterize the glucuronidation pathway of arctigenin (AR) in human liver microsomes (HLM) and human intestine microsomes (HIM).
  
  
  METHODS
  HLM and HIM incubation systems were employed to catalyse the formation of AR glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards AR was screened. A combination of chemical inhibition assay and kinetic analysis was used to determine the UGT isoforms involved in the glucuronidation of AR in HLM and HIM.
  
  
  RESULTS
  AR could be extensively metabolized to one mono-glucuronide in HLM and HIM. The mono-glucuronide was biosynthesized and characterized as 4'-O-glucuronide. UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and 2B17 participated in the formation of 4'-O-G, while UGT2B17 demonstrated the highest catalytic activity in this biotransformation. Both kinetic analysis and chemical inhibition assays demonstrated that UGT1A9, UGT2B7 and UGT2B17 played important roles in AR-4'-O-glucuronidation in HLM. Furthermore, HIM demonstrated moderate efficiency for AR-4'-O-glucuronidation, implying that AR may undergo a first-pass metabolism during the absorption process.
  
  
  CONCLUSIONS
  UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4'-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM.
authors.affiliation: Department of Integrated Traditional and Western Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Yang-Liu
authors.initials: YL
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Integrated Traditional and Western Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Department of Integrated Traditional and Western Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D001711:Biotransformation; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes; D007700:Kinetics; D017705:Lignans / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D015778:Minor Histocompatibility Antigens; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D020719:Glucuronides; D007527:Isoenzymes; D017705:Lignans; D015778:Minor Histocompatibility Antigens; D011994:Recombinant Proteins; C000715591:UGT1A9 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C500513:UGT2B17 protein, human; C071942:arctigenin
keywords: UDP-glucuronosyltransferases; arctigenin; glucuronidation; human intestine microsomes; human liver microsomes