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J Pharm Pharmacol. 2015 Dec;67(12):1673-81. doi: 10.1111/jphp.12483. Epub 2015 Sep 26.

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin.

Author information

1
Department of Integrated Traditional and Western Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, China.
2
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
3
Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China.

Abstract

OBJECTIVES:

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.

KEY FINDINGS:

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.

CONCLUSION:

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.

KEYWORDS:

UDP-glucuronosyltransferases; arctigenin; glucuronidation; human intestine microsomes; human liver microsomes

PMID:
26407805
DOI:
10.1111/jphp.12483
[Indexed for MEDLINE]

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