Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification

Jodi M. Maglich, Catherine M. Stoltz, Bryan Goodwin, Diane Hawkins-Brown, John T. Moore, Steven A. Kliewer

Research output: Contribution to journalArticle

542 Citations (Scopus)

Abstract

The nuclear pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play central roles in protecting the body against environmental chemicals (xenobiotics). PXR and CAR are activated by a wide range of xenobiotics and regulate cytochrome P450 and other genes whose products are involved in the detoxification of these chemicals. In this report, we have used receptor-selective agonists together with receptor-null mice to identify PXR and CAR target genes in the liver and small intestine. Our results demonstrate that PXR and CAR regulate overlapping but distinct sets of genes involved in all phases of xenobiotic metabolism, including oxidative metabolism, conjugation, and transport. Among the murine genes regulated by PXR were those encoding PXR and CAR. We provide evidence that PXR regulates a similar program of genes involved in xenobiotic metabolism in human liver. Among the genes regulated by PXR in primary human hepatocytes were the aryl hydrocarbon receptor and its target genes CYP1A1 and CYP1A2. These findings underscore the importance of these two nuclear receptors in defending the body against a broad array of potentially harmful xenobiotics.

Original languageEnglish (US)
Pages (from-to)638-646
Number of pages9
JournalMolecular Pharmacology
Volume62
Issue number3
DOIs
StatePublished - Sep 1 2002

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Xenobiotics
Genes
Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP1A1
pregnane X receptor
constitutive androstane receptor
Liver
Cytoplasmic and Nuclear Receptors
Cytochrome P-450 Enzyme System
Small Intestine
Hepatocytes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. / Maglich, Jodi M.; Stoltz, Catherine M.; Goodwin, Bryan; Hawkins-Brown, Diane; Moore, John T.; Kliewer, Steven A.

In: Molecular Pharmacology, Vol. 62, No. 3, 01.09.2002, p. 638-646.

Research output: Contribution to journalArticle

Maglich, Jodi M. ; Stoltz, Catherine M. ; Goodwin, Bryan ; Hawkins-Brown, Diane ; Moore, John T. ; Kliewer, Steven A. / Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. In: Molecular Pharmacology. 2002 ; Vol. 62, No. 3. pp. 638-646.
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