Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene

Biochem Pharmacol. 2011 Dec 1;82(11):1771-80. doi: 10.1016/j.bcp.2011.08.023. Epub 2011 Sep 6.


Metformin is widely used in the treatment of type-2 diabetes. The pleotropic effects of metformin on glucose and lipid metabolism have been proposed to be mediated by the activation of AMP-activated protein kinase (AMPK) and the subsequent up-regulation of small heterodimer partner (SHP). SHP suppresses the functions of several nuclear receptors involved in the regulation of hepatic metabolism, including pregnane X receptor (PXR), which is referred to as a "master regulator" of drug/xenobiotic metabolism. In this study, we hypothesize that metformin suppresses the expression of CYP3A4, a main detoxification enzyme and a target gene of PXR, due to SHP up-regulation. We employed various gene reporter assays in cell lines and qRT-PCR in human hepatocytes and in Pxr(-/-) mice. We show that metformin dramatically suppresses PXR-mediated expression of CYP3A4 in hepatocytes. Consistently, metformin significantly suppressed the up-regulation of Cyp3a11 mRNA in the liver and intestine of wild-type mice, but not in Pxr(-/-) mice. A mechanistic investigation of the phenomenon showed that metformin does not significantly up-regulate SHP in human hepatocytes. We further demonstrate that AMPK activation is not involved in this process. We show that metformin disrupts PXR's interaction with steroid receptor coactivator-1 (SRC1) in a two-hybrid assay independently of the PXR ligand binding pocket. Metformin also inhibited vitamin D receptor-, glucocorticoid receptor- and constitutive androstane receptor (CAR)-mediated induction of CYP3A4 mRNA in human hepatocytes. We show, therefore, a suppressive effect of metformin on PXR and other ligand-activated nuclear receptors in transactivation of the main detoxification enzyme CYP3A4 in human hepatocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Cells, Cultured
  • Constitutive Androstane Receptor
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 CYP3A / metabolism
  • Genes, Reporter
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivators / metabolism
  • Pregnane X Receptor
  • RNA, Messenger / metabolism
  • Receptors, Calcitriol / physiology
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Glucocorticoid / physiology
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*
  • Reflex, Righting / drug effects
  • Signal Transduction
  • Transcriptional Activation


  • Constitutive Androstane Receptor
  • Hypoglycemic Agents
  • Membrane Proteins
  • Nuclear Receptor Coactivators
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Calcitriol
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Receptors, Steroid
  • nuclear receptor subfamily 0, group B, member 2
  • Metformin
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • AMP-Activated Protein Kinases