TY - JOUR
T1 - Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands
AU - Moore, Linda B.
AU - Parks, Derek J.
AU - Jones, Stacey A.
AU - Bledsoe, Randy K.
AU - Consler, Thomas G.
AU - Stimmel, Julie B.
AU - Goodwin, Bryan
AU - Liddle, Christopher
AU - Blanchard, Steven G.
AU - Willson, Timothy M.
AU - Collins, Jon L.
AU - Kliewer, Steven A.
PY - 2000/5/19
Y1 - 2000/5/19
N2 - 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 asteroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.
AB - 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 asteroid 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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U2 - 10.1074/jbc.M001215200
DO - 10.1074/jbc.M001215200
M3 - Article
C2 - 10748001
AN - SCOPUS:0034685779
SN - 0021-9258
VL - 275
SP - 15122
EP - 15127
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -