PMID- 21920351
OWN - NLM
STAT- MEDLINE
DCOM- 20120116
LR  - 20211203
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 82
IP  - 11
DP  - 2011 Dec 1
TI  - Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of 
      CYP3A4 gene.
PG  - 1771-80
LID - 10.1016/j.bcp.2011.08.023 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Krausova, Lucie
AU  - Krausova L
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, 
      Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, CZ-500 05, Czech 
      Republic.
FAU - Stejskalova, Lucie
AU  - Stejskalova L
FAU - Wang, Hongwei
AU  - Wang H
FAU - Vrzal, Radim
AU  - Vrzal R
FAU - Dvorak, Zdenek
AU  - Dvorak Z
FAU - Mani, Sridhar
AU  - Mani S
FAU - Pavek, Petr
AU  - Pavek P
LA  - eng
GR  - R01 CA127231/CA/NCI NIH HHS/United States
GR  - R01 CA127231-03/CA/NCI NIH HHS/United States
GR  - R01CA 127231/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110906
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Constitutive Androstane Receptor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Receptor Coactivators)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Receptors, Steroid)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
RN  - 9100L32L2N (Metformin)
RN  - EC 1.14.14.1 (Cyp3a11 protein, mouse)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/physiology
MH  - Animals
MH  - Cells, Cultured
MH  - Constitutive Androstane Receptor
MH  - Cytochrome P-450 CYP3A/*genetics/metabolism
MH  - Genes, Reporter
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Membrane Proteins/*genetics/metabolism
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Nuclear Receptor Coactivators/metabolism
MH  - Pregnane X Receptor
MH  - RNA, Messenger/metabolism
MH  - Receptors, Calcitriol/physiology
MH  - Receptors, Cytoplasmic and Nuclear/metabolism/physiology
MH  - Receptors, Glucocorticoid/physiology
MH  - Receptors, Steroid/genetics/*physiology
MH  - Reflex, Righting/drug effects
MH  - Signal Transduction
MH  - Transcriptional Activation
PMC - PMC3205227
MID - NIHMS323022
EDAT- 2011/09/17 06:00
MHDA- 2012/01/17 06:00
PMCR- 2012/12/01
CRDT- 2011/09/17 06:00
PHST- 2011/07/30 00:00 [received]
PHST- 2011/08/25 00:00 [revised]
PHST- 2011/08/29 00:00 [accepted]
PHST- 2011/09/17 06:00 [entrez]
PHST- 2011/09/17 06:00 [pubmed]
PHST- 2012/01/17 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - S0006-2952(11)00674-5 [pii]
AID - 10.1016/j.bcp.2011.08.023 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2011 Dec 1;82(11):1771-80. doi: 10.1016/j.bcp.2011.08.023. 
      Epub 2011 Sep 6.