Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9

Xenobiotica. 2012 Oct;42(10):1001-8. doi: 10.3109/00498254.2012.681814. Epub 2012 May 16.

Abstract

1. Human exposure to magnolol can reach a high dose in daily life. Our previous studies indicated that magnolol showed high affinities to several UDP-glucuronosyltransferases (UGTs) This study was designed to examine the in vitro inhibitory effects of magnolol on UGTs, and further to evaluate the possibility of the in vivo inhibition that might happen. 2. Assays with recombinant UGTs and human liver microsomes (HLM) indicated that magnolol (10 µM) can selectively inhibit activities of UGT1A9 and extra-hepatic UGT1A7. Inhibition of magnolol on UGT1A7 followed competitive inhibition mechanism, while the inhibition on UGT1A9 obeyed either competitive or mixed inhibition mechanism, depending on substrates. The K(i) values for UGT1A7 and 1A9 are all in nanomolar ranges, lower than possible magnolol concentrations in human gut lumen and blood, indicating the in vivo inhibition on these two enzymes would likely occur. 3. In conclusion, UGT1A7 and 1A9 can be strongly inhibited by magnolol, raising the alarm for safe application of magnolol and traditional Chinese medicines containing magnolol. Additionally, given that UGT1A7 is an extra-hepatic enzyme, magnolol can serve as a selective UGT1A9 inhibitor that will act as a new useful tool in future hepatic glucuronidation phenotyping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis / drug effects*
  • Biomarkers / metabolism
  • Biphenyl Compounds / blood
  • Biphenyl Compounds / pharmacology*
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacology*
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / metabolism
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Glucuronosyltransferase / metabolism
  • Humans
  • Kinetics
  • Lignans / blood
  • Lignans / pharmacology*
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Recombinant Proteins / metabolism
  • UDP-Glucuronosyltransferase 1A9

Substances

  • Biomarkers
  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Lignans
  • Recombinant Proteins
  • UGT1A9 protein, human
  • magnolol
  • Glucuronosyltransferase
  • UDP-Glucuronosyltransferase 1A9
  • UDP-glucuronosyltransferase, UGT1A7