Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands

Linda B. Moore, Derek J. Parks, Stacey A. Jones, Randy K. Bledsoe, Thomas G. Consler, Julie B. Stimmel, Bryan Goodwin, Christopher Liddle, Steven G. Blanchard, Timothy M. Willson, Jon L. Collins, Steven A. Kliewer

Research output: Contribution to journalArticle

707 Scopus citations

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 asteroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.

Original languageEnglish (US)
Pages (from-to)15122-15127
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number20
DOIs
StatePublished - May 19 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C., Blanchard, S. G., Willson, T. M., Collins, J. L., & Kliewer, S. A. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. Journal of Biological Chemistry, 275(20), 15122-15127. https://doi.org/10.1074/jbc.M001215200