Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Huang, Wendong; Zhang, Jun; Chua, Steven S.; Qatanani, Mohammed; Han, Yushui; Granata, Riccarda; Moore, David D.

doi:10.1073/pnas.0630614100

Cited by 359 publications

(282 citation statements)

References 46 publications

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“…Both receptors protect the body from the deleterious accumulation of bilirubin [61,62] and bile acids [63] through hepatic induction of several enzyme genes. Additionally, many CAR and PXR target genes, including CYP3A and CYP2B, are involved in steroid hormone metabolism and their induction could contribute to the endocrine disruption activities of drugs and contaminants [64,65].…”

Section: Discussionmentioning

confidence: 99%

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Eveillard¹,

Mselli-Lakhal²,

Mogha³

et al. 2009

Biochemical Pharmacology

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To cite this version:Alexandre Eveillard, Laïla Mselli-Lakhal, Ariane Mogha, Frédéric Lasserre, Arnaud Polizzi, et al.. Di-(2-ethylhexyl)-phthalate (DEHP) activates the Constitutive Androstane Receptor (CAR): a novel signalling pathway sensitive to phthalates. Biochemical Pharmacology, Elsevier, 2009, 77 (11) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Eveillard¹,

Mselli-Lakhal²,

Mogha³

et al. 2009

Biochemical Pharmacology

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“…Finally, activation of both PXR and CAR increases clearance of bilirubin from hepatocytes [42,57]. Bilirubin does not directly bind to either CAR or PXR [57]. Instead, bilirubin activates CAR indirectly by promoting cytoplasmic-nuclear translocation, similar to the effects described for phenobarbital on CAR [57].…”

mentioning

confidence: 85%

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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“…Studies using CAR-defective mice demonstrated that all proteins involved in bilirubin clearance by hepatocytes are under the control of CAR including OATP1B1 and 1B3 (uptake transporters for bilirubin and bilirubin monoglucuronide into hepatocytes), GSTA1/2 (involved in intracellular binding of bilirubin), bilirubin conjugating UGT1A1 and Mrp2 (responsible for biliary secretion of bilirubin conjugates [78]. Low CAR expression in the fetus may contribute to neonatal jaundice [78].…”

Section: Possible Autoregulatory Control Of Ugt1a1 By Bilirubinmentioning

confidence: 99%

“…Low CAR expression in the fetus may contribute to neonatal jaundice [78]. Bilirubin is the toxic end product of heme catabolism.…”

Section: Possible Autoregulatory Control Of Ugt1a1 By Bilirubinmentioning

confidence: 99%

“…A significant amount of bilirubin is produced every day (250-400 mg in adult humans) which is cleared in the liver by the above CARregulated XME system. Interestingly, bilirubin is an activator of CAR [78] and of AhR ( [8], for references). In support of the role of these LATFs in bilirubin catabolism, 10 phenobarbital-type inducers in human primary hepatocyte cultures [79].…”

Section: Possible Autoregulatory Control Of Ugt1a1 By Bilirubinmentioning

confidence: 99%

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From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Cited by 359 publications

References 46 publications

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

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

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

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