The Peroxisome Proliferator Response Element of the Gene Encoding the Peroxisomal β-Oxidation Enzyme Enoyl-CoA Hydratase/3-Hydroxyacyl-CoA Dehydrogenase Is a Target for Constitutive Androstane Receptor β/9-cis-Retinoic Acid Receptor-mediated Transactivation

Kassam, Altaf; Winrow, Christopher J.; Fernandez-Rachubinski, F; Capone, John P.; Rachubinski, Richard A.

doi:10.1074/jbc.275.6.4345

Cited by 47 publications

(43 citation statements)

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“…Subsequently, it was found that the receptor could transactivate via a DR4 element in CYP2B genes (9) and a DR1 peroxisome proliferator response element in the enoyl-CoA hydratase/3-hydroxy acyl-CoA dehydrogenase gene (27). Here we show that CAR can transactivate CYP gene expression in response to PB via DR4 and DR3 elements.…”

Section: Discussionmentioning

confidence: 70%

Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics

Smirlis

Muangmoonchai

Edwards

et al. 2001

Journal of Biological Chemistry

100

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The mechanisms by which different classes of chemicals induce the same cytochrome P450 (CYP) or the same chemical differentially induces more than one CYP are not well understood. We show that in primary hepatocytes and in vivo in liver (transfected by particlemediated delivery) two orphan nuclear receptors, constitutive androstane receptor and pregnane X receptor (PXR1), transactivate a CYP gene via the same response element in a xenobiotic-specific manner. The constitutive androstane receptor mediates the barbiturate activation of expression of CYP2B1 and CYP3A1. PXR1 activates both genes in response to synthetic steroids. To exert their effect the receptors bind to the same direct repeat site (DR4) within the phenobarbital response element of the CYP2B1 promoter and to the same DR3 site in the pregnane X response element of CYP3A1. The receptors are therefore promiscuous with respect to DNA binding but not ligand binding. Differences in enhancer half-site spacing may influence the efficiency of interactions between the receptor and the transcription machinery and hence form the basis for the differential induction of CYP2B1 and CYP3A1 in response to barbiturates and synthetic steroids.Cytochromes P450 (CYPs) 1 are a superfamily of proteins, members of which catalyze the metabolism of a wide range of endogenous and exogenous chemicals (1). CYP-mediated detoxification is a key defense mechanism whereby organisms protect themselves from the potentially harmful effects of foreign hydrophobic chemicals to which they are exposed. The xenobiotics are converted to more hydrophilic compounds, which are then more easily excreted (2). Many of these xenobiotics serve as inducers of the particular CYP required for their metabolism. Induction of CYPs is mediated primarily at the transcriptional level by the interaction of ligand-nuclear receptor complexes with enhancer sequences that lie upstream of CYP gene promoters (reviewed in Refs. 3 and 4). A single CYP can be induced to different extents by different classes of chemicals, and a single chemical can differentially induce more than one CYP. For instance, CYP2B1 and CYP3A1, members of two different CYP subfamilies, can both be induced in the liver by the barbiturate phenobarbital (PB) and by the structurally unrelated synthetic pregnane pregnenolone 16␣-carbonitrile (PCN). CYP2B1 is induced to a greater extent by PB than by PCN (5), whereas CYP3A1 is induced more highly by PCN than by PB (6). Induction of CYP2B1 in response to PB is mediated by the interaction of the constitutive androstane receptor (CAR) (7) with a phenobarbital response element (PBRE) (8, 9), and that of CYP3A1 in response to PCN by binding of the pregnane X receptor (PXR1) to a pregnane X response element (PXRE) (10 -13). However, no PBRE has been identified in the flanking regions of the CYP3A1 gene, and a PXRE has not been identified in the CYP2B1 gene. The mechanisms of induction of CYP2B1 by PCN and of CYP3A1 by PB are not known.Here we show that CAR and PXR1 can transactivate the CYP2B1 gene b...

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Section: Discussionmentioning

confidence: 70%

Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics

Smirlis

Muangmoonchai

Edwards

et al. 2001

Journal of Biological Chemistry

100

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“…However, a number of findings suggest a role for CAR and PXR in this process. First, CAR can bind to DNA-elements overlapping with those for PPAR in the promoter of enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, the second enzyme of peroxisomal fatty acid -oxidation [111].…”

Section: Nr1i Subfamily Members Regulate Lipid Levels In the Livermentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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“…En consé-quence, CAR pourrait être un médiateur universel de l'effet du phénobarbital chez les rongeurs et chez l'homme. En outre, CAR permet la surexpression d'autres gènes en réponse au phénobarbital, dont le gène codant pour l'UDP-glucuronosyl transférase et l'énoyl-CoA hydratase [36]. Cependant, la présence éventuelle de séquences de type DR4 n'a pas été rapportée pour ces gènes, bien que des séquences de type DR1 soient présentes dans le promoteur de l'énoyl-CoA hydratase [37].…”

Section: T C T G T a C T T T C C T G A C C T T G G C A C A G T G C C unclassified

Les récepteurs nucléaires CAR et PXR contrôlent l’induction des cytochromes P450 par le phénobarbital

Corcos¹,

Brey

Corcos

2002

Med Sci (Paris)

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The Peroxisome Proliferator Response Element of the Gene Encoding the Peroxisomal β-Oxidation Enzyme Enoyl-CoA Hydratase/3-Hydroxyacyl-CoA Dehydrogenase Is a Target for Constitutive Androstane Receptor β/9-cis-Retinoic Acid Receptor-mediated Transactivation

Cited by 47 publications

References 40 publications

Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics

Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Les récepteurs nucléaires CAR et PXR contrôlent l’induction des cytochromes P450 par le phénobarbital

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