Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.
J Biol Chem
; 275(20): 15122-7, 2000 May 19.
Article
in En
| MEDLINE
| ID: mdl-10748001
ABSTRACT
Xenobiotics induce the transcription of cytochromes P450 (CYPs) 2B and 3A through the constitutive androstane receptor (CAR; NR1I3) and pregnane X receptor (PXR; NR1I2), respectively. In this report, we have systematically compared a series of xenobiotics and natural steroids for their effects on mouse and human CAR and PXR. Our results demonstrate dual regulation of PXR and CAR by a subset of compounds that affect CYP expression. Moreover, there are marked pharmacological differences between the mouse (m) and human (h) orthologs of both CAR and PXR. For example, the planar hydrocarbon 1, 4-bis[2-(3,5-dichloropyridyl-oxy)]benzene activates mCAR and hPXR but has little or no activity on hCAR and mPXR. In contrast, the CAR deactivator androstanol activates both mouse and human PXR. Similarly, the PXR activator clotrimazole is a potent deactivator of hCAR. Using radioligand binding and fluorescence resonance energy transfer assays, we demonstrate that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors. Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Steroids
/
Transcription Factors
/
Aryl Hydrocarbon Hydroxylases
/
Xenobiotics
/
Receptors, Steroid
/
Receptors, Cytoplasmic and Nuclear
Limits:
Animals
/
Humans
Language:
En
Journal:
J Biol Chem
Year:
2000
Document type:
Article
Affiliation country:
United States