Alterations in the distribution and orexigenic effects of dexamethasone in CAR-null mice

Pharmacology, Biochemistry, and Behavior
Mohammed QatananiDavid D Moore

Abstract

The constitutive androstane receptor (CAR, NR1I3) has emerged as an important regulator of drug metabolism. CAR responds to a wide spectrum of xenobiotics by inducing expression of cytochrome P450 (CYP) enzymes and a number of other proteins responsible for drug metabolism in the liver. The xenosensor function of CAR overlaps with that of the pregnane X receptor (PXR), another xenobiotic receptor that belongs to the nuclear hormone superfamily. We observed that injection of dexamethasone (Dex), a ligand for the glucocorticoid receptor (GR) and PXR but not CAR, results in an unexpected twofold increase in the stomach weight of CAR-null animals relative to wild-type animals. Here, we show that CAR knockout mice have elevated levels of Dex in the brain, resulting in a more rapid and robust increase in the hypothalamic expression of the GR-responsive target genes encoding neuropeptide Y (NPY) and neuropeptide Y receptor subtype 1 (NPY-R1). As expected, this is accompanied by a higher increase in the food intake of the CAR-null animals. The data described here highlight the complexity of the overlapping functions of CAR and PXR.

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Citations

Jan 10, 2006·Methods in Enzymology·Haibiao GongWen Xie
Dec 8, 2004·Archives of Biochemistry and Biophysics·Christoph Handschin, Urs A Meyer
Dec 30, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Scott S AuerbachCurtis J Omiecinski

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