The pregnane X receptor: A promiscuous xenobiotic receptor that has diverged during evolution

Stacey A. Jones, Linda B. Moore, Jennifer L. Shenk, G. Bruce Wisely, Geraldine A. Hamilton, David D. McKee, Nicholas C O Tomkinson, Edward L. LeCluyse, Millard H. Lambert, Timothy M. Willson, Steven A. Kliewer, John T. Moore

Research output: Contribution to journalArticle

567 Citations (Scopus)

Abstract

Transcription of genes encoding cytochrome P450 3A (CYP3A) monooxygenases is induced by a variety of xenobiotics and natural steroids. There are marked differences in the compounds that induce CYP3A gene expression between species. Recently, the mouse and human pregnane X receptor (PXR) were shown to be activated by compounds that induce CYP3A expression. However, most studies of CYP3A regulation have been performed using rabbit and rat hepatocytes. Here, we report the cloning and characterization of PXR from these two species. PXR is remarkably divergent between species, with the rabbit, rat, and human receptors sharing only approximately 80% amino acid identity in their ligand-binding domains. This sequence divergence is reflected by marked pharmacological differences in PXR activation profiles. For example, the macrolide antibiotic rifampicin, the antidiabetic drug troglitazone, and the hypocholesterolemic drug SR12813 are efficacious activators of the human and rabbit PXR but have little activity on the rat and mouse PXR. Conversely, pregnane 16α-carbonitrile is a more potent activator of the rat and mouse PXR than the human and rabbit receptor. The activities of xenobiotics in PXR activation assays correlate well with their ability to induce CYP3A expression in primary hepatocytes. Through the use of a novel scintillation proximity binding assay, we demonstrate that many of the compounds that induce CYP3A expression bind directly to human PXR. These data establish PXR as a promiscuous xenobiotic receptor that has diverged during evolution.

Original languageEnglish (US)
Pages (from-to)27-39
Number of pages13
JournalMolecular Endocrinology
Volume14
Issue number1
DOIs
StatePublished - 2000

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Xenobiotics
Cytochrome P-450 CYP3A
Rabbits
troglitazone
Hepatocytes
pregnane X receptor
Pregnanes
Macrolides
Rifampin
Mixed Function Oxygenases
Hypoglycemic Agents
Organism Cloning
Steroids
Pharmacology
Anti-Bacterial Agents
Ligands
Gene Expression
Amino Acids

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Jones, S. A., Moore, L. B., Shenk, J. L., Wisely, G. B., Hamilton, G. A., McKee, D. D., ... Moore, J. T. (2000). The pregnane X receptor: A promiscuous xenobiotic receptor that has diverged during evolution. Molecular Endocrinology, 14(1), 27-39. https://doi.org/10.1210/me.14.1.27

The pregnane X receptor : A promiscuous xenobiotic receptor that has diverged during evolution. / Jones, Stacey A.; Moore, Linda B.; Shenk, Jennifer L.; Wisely, G. Bruce; Hamilton, Geraldine A.; McKee, David D.; Tomkinson, Nicholas C O; LeCluyse, Edward L.; Lambert, Millard H.; Willson, Timothy M.; Kliewer, Steven A.; Moore, John T.

In: Molecular Endocrinology, Vol. 14, No. 1, 2000, p. 27-39.

Research output: Contribution to journalArticle

Jones, SA, Moore, LB, Shenk, JL, Wisely, GB, Hamilton, GA, McKee, DD, Tomkinson, NCO, LeCluyse, EL, Lambert, MH, Willson, TM, Kliewer, SA & Moore, JT 2000, 'The pregnane X receptor: A promiscuous xenobiotic receptor that has diverged during evolution', Molecular Endocrinology, vol. 14, no. 1, pp. 27-39. https://doi.org/10.1210/me.14.1.27
Jones, Stacey A. ; Moore, Linda B. ; Shenk, Jennifer L. ; Wisely, G. Bruce ; Hamilton, Geraldine A. ; McKee, David D. ; Tomkinson, Nicholas C O ; LeCluyse, Edward L. ; Lambert, Millard H. ; Willson, Timothy M. ; Kliewer, Steven A. ; Moore, John T. / The pregnane X receptor : A promiscuous xenobiotic receptor that has diverged during evolution. In: Molecular Endocrinology. 2000 ; Vol. 14, No. 1. pp. 27-39.
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