Abstract
The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two closely related and liver-enriched nuclear hormone receptors originally defined as xenobiotic receptors. PXR and CAR regulate the transcription of drug-metabolizing enzymes and transporters, which are essential in protecting our bodies from the accumulation of harmful chemicals. An increasing body of evidence suggests that PXR and CAR also have an endobiotic function that impacts energy homeostasis through the regulation of glucose and lipids metabolism. Of note and in contrast, disruptions of energy homeostasis, such as those observed in obesity and diabetes, also have a major impact on drug metabolism. This review will focus on recent progress in our understanding of the integral role of PXR and CAR in drug metabolism and energy homeostasis.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES014626]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK076962]; and a Molecular Pharmacology Fellowship funded by the University of Pittsburgh Department of Pharmacology and Chemical Biology.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035568.
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ABBREVIATIONS:
- P450
- cytochrome P450
- PXR
- pregnane X receptor
- SULTs
- sulfotransferases
- CAR
- constitutive androstane receptor
- PB
- phenobarbital
- TCPOBOP
- 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene
- LXR
- liver X receptor
- NASH
- nonalcoholic steatohepatitis
- SREBP-1
- sterol regulatory element-binding protein 1
- AMPK
- AMP-activated protein kinase
- PAR bZip
- PAR-domain basic leucine zipper
- PGC-1α
- peroxisome-proliferator-activated-receptor-γ-coactivator-1α
- FOXO1
- Forkhead box O1 protein
- CPR
- cytochrome P450 reductase
- PPARγ2
- peroxisome proliferator-activated receptor γ2
- TH
- thyroid hormone
- PCN
- pregnenolone-16α-carbonitrile
- CPT1α
- carnitine palmitoyltransferase 1α
- HMGCS2
- 3-hydroxy-3-methylglutarate-CoA synthase 2
- FoxA2
- Forkhead box A2
- CREB
- cAMP response element-binding protein
- PEPCK
- phosphoenolpyruvate carboxykinase
- AICAR
- 5-amino-1-β-d-ribofuranosyl-1H-imidazole-4-carboxamide.
- Received July 18, 2010.
- Accepted August 23, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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- Pregnane X Receptor and Constitutive Androstane Receptor As Master Regulators of Drug Metabolism and Drug Transporter
- Drug Metabolism Can Be Affected by Energy Metabolism
- Energy Metabolism Can Be Affected by Drug Metabolism and Xenobiotic Receptors PXR and CAR
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