Identification of Human UDP-Glucuronosyltransferase 1A4 as the Major Isozyme Responsible for the Glucuronidation of 20(S)-Protopanaxadiol in Human Liver Microsomes

Int J Mol Sci. 2016 Mar 9;17(3):205. doi: 10.3390/ijms17030205.

Abstract

20(S)-protopanaxadiol (PPD), one of the representative aglycones of ginsenosides, has a broad spectrum of pharmacological activities. Although phase I metabolism has been investigated extensively, information regarding phase II metabolism of this compound remains to be elucidated. Here, a glucuronidated metabolite of PPD in human liver microsomes (HLMs) and rat liver microsomes (RLMs) was unambiguously identified as PPD-3-O-β-D-glucuronide by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry. The chemical inhibition and recombinant human UDP-Glucuronosyltransferase (UGT) isoforms assay showed that the PPD glucuronidation was mainly catalyzed by UGT1A4 in HLM, whereas UGT1A3 showed weak catalytic activity. In conclusion, PPD-3-O-β-D-glucuronide was first identified as the principal glucuronidation metabolite of PPD in HLMs, which was catalyzed by UGT1A4.

Keywords: 20(S)-protopanaxadiol; UGT1A4; glucuronidation; liquid chromatography-mass spectrometry (LC-MS); liver microsomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ginsenosides / metabolism*
  • Glucuronides / metabolism
  • Glucuronosyltransferase / chemistry
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Liver / enzymology*
  • Liver / metabolism
  • Microsomes / enzymology*
  • Microsomes / metabolism
  • Rats
  • Sapogenins / metabolism*
  • Uridine Diphosphate / metabolism

Substances

  • Ginsenosides
  • Glucuronides
  • Isoenzymes
  • Sapogenins
  • ginsenoside 20S-protopanaxatriol
  • Uridine Diphosphate
  • Glucuronosyltransferase