Constitutive androstane receptor pathway (Bos taurus)

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10, 26, 34Phase 2 metabolismTranscriptionDrug and steroid metabolismMulti-drug resistanceOtherLigandNR1I3RXRAHSP90AA1PPP2R4NR1I332, 35LigandHSP90AA1GenesTATA boxPBREMRXRANR1I3LigandDNAJC7DNAJC7NCOA6SP1NCOA1PPARGC1ANCOA2SMC1ACoregulatorsCAR target genesCYP2C91923ABCB1UGT1A1341ABCC245CYP2A63CYP4A1145CYP2C19SULT1A12342GSTA2CYP3A53SULT2A123CYP3A42423ALAS1EHHADH3CYP2B64523ABCC345UGT1A4UGT1A630UGT1A930UGT1A33030FOXO131


Description

The Constitutive Androstane Receptor (CAR) is a nuclear receptor and functions as a sensor for xenobiotics. It regulates transcription of genes encoding proteins in metabolism and excretion of xenobiotics

Comments

 

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2875(79890) with a 89.0% conversion rate.

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Ontology Terms

 

Bibliography

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  1. Hariparsad N, Chu X, Yabut J, Labhart P, Hartley DP, Dai X, Evers R; ''Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes.''; Nucleic Acids Res, 2009 PubMed Europe PMC Scholia
  2. Vezina CM, Walker NJ, Olson JR; ''Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression.''; Environ Health Perspect, 2004 PubMed Europe PMC Scholia
  3. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT; ''Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  4. Cai Y, Konishi T, Han G, Campwala KH, French SW, Wan YJ; ''The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways.''; Eur J Pharm Sci, 2002 PubMed Europe PMC Scholia
  5. Nilsson S, Gustafsson JÅ; ''Estrogen receptors: therapies targeted to receptor subtypes.''; Clin Pharmacol Ther, 2011 PubMed Europe PMC Scholia
  6. Tachibana K, Kobayashi Y, Tanaka T, Tagami M, Sugiyama A, Katayama T, Ueda C, Yamasaki D, Ishimoto K, Sumitomo M, Uchiyama Y, Kohro T, Sakai J, Hamakubo T, Kodama T, Doi T; ''Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms.''; Nucl Recept, 2005 PubMed Europe PMC Scholia
  7. Haarmann-Stemmann T, Bothe H, Abel J; ''Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways.''; Biochem Pharmacol, 2009 PubMed Europe PMC Scholia
  8. Hockley SL, Arlt VM, Brewer D, Te Poele R, Workman P, Giddings I, Phillips DH; ''AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines.''; Chem Res Toxicol, 2007 PubMed Europe PMC Scholia
  9. Rodríguez-Sosa M, Elizondo G, López-Durán RM, Rivera I, Gonzalez FJ, Vega L; ''Over-production of IFN-gamma and IL-12 in AhR-null mice.''; FEBS Lett, 2005 PubMed Europe PMC Scholia
  10. Willson TM, Kliewer SA; ''PXR, CAR and drug metabolism.''; Nat Rev Drug Discov, 2002 PubMed Europe PMC Scholia
  11. Han S, Chiang JY; ''Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.''; Drug Metab Dispos, 2009 PubMed Europe PMC Scholia
  12. Drocourt L, Ourlin JC, Pascussi JM, Maurel P, Vilarem MJ; ''Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes.''; J Biol Chem, 2002 PubMed Europe PMC Scholia
  13. Li AC, Glass CK; ''PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis.''; J Lipid Res, 2004 PubMed Europe PMC Scholia
  14. Gadaleta RM, van Mil SW, Oldenburg B, Siersema PD, Klomp LW, van Erpecum KJ; ''Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease.''; Biochim Biophys Acta, 2010 PubMed Europe PMC Scholia
  15. Wang JC, Derynck MK, Nonaka DF, Khodabakhsh DB, Haqq C, Yamamoto KR; ''Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes.''; Proc Natl Acad Sci U S A, 2004 PubMed Europe PMC Scholia
  16. Köhle C, Bock KW; ''Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2.''; Biochem Pharmacol, 2007 PubMed Europe PMC Scholia
  17. Hashimoto K, Mori M; ''Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review].''; Endocr J, 2011 PubMed Europe PMC Scholia
  18. Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B, Bendixen C, Mandrup S, Kristiansen K; ''Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation.''; Biochem J, 2002 PubMed Europe PMC Scholia
  19. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT; ''Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  20. Jeon MS, Esser C; ''The murine IL-2 promoter contains distal regulatory elements responsive to the Ah receptor, a member of the evolutionarily conserved bHLH-PAS transcription factor family.''; J Immunol, 2000 PubMed Europe PMC Scholia
  21. Rochette-Egly C, Germain P; ''Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs).''; Nucl Recept Signal, 2009 PubMed Europe PMC Scholia
  22. Mandard S, Müller M, Kersten S; ''Peroxisome proliferator-activated receptor alpha target genes.''; Cell Mol Life Sci, 2004 PubMed Europe PMC Scholia
  23. Pavek P, Dvorak Z; ''Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues.''; Curr Drug Metab, 2008 PubMed Europe PMC Scholia
  24. Echchgadda I, Song CS, Oh T, Ahmed M, De La Cruz IJ, Chatterjee B; ''The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase.''; Mol Endocrinol, 2007 PubMed Europe PMC Scholia
  25. Weiss C, Faust D, Dürk H, Kolluri SK, Pelzer A, Schneider S, Dietrich C, Oesch F, Göttlicher M; ''TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38-MAPK-dependent pathway.''; Oncogene, 2005 PubMed Europe PMC Scholia
  26. Fijten RR, Jennen DG, van Delft JH; ''Pathways for ligand activated nuclear receptors to unravel the genomic responses induced by hepatotoxicants.''; Curr Drug Metab, 2013 PubMed Europe PMC Scholia
  27. Gadaleta RM, van Mil SW, Oldenburg B, Siersema PD, Klomp LW, van Erpecum KJ; ''Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease.''; Biochim Biophys Acta, 2010 PubMed Europe PMC Scholia
  28. Weiss C, Faust D, Schreck I, Ruff A, Farwerck T, Melenberg A, Schneider S, Oesch-Bartlomowicz B, Zatloukalová J, Vondrácek J, Oesch F, Dietrich C; ''TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A.''; Oncogene, 2008 PubMed Europe PMC Scholia
  29. Le Vee M, Jouan E, Fardel O; ''Involvement of aryl hydrocarbon receptor in basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced expression of target genes in primary human hepatocytes.''; Toxicol In Vitro, 2010 PubMed Europe PMC Scholia
  30. Bock KW; ''From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans.''; Biochem Pharmacol, 2011 PubMed Europe PMC Scholia
  31. Kodama S, Koike C, Negishi M, Yamamoto Y; ''Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes.''; Mol Cell Biol, 2004 PubMed Europe PMC Scholia
  32. Cai Y, Konishi T, Han G, Campwala KH, French SW, Wan YJ; ''The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways.''; Eur J Pharm Sci, 2002 PubMed Europe PMC Scholia
  33. Mimura J, Fujii-Kuriyama Y; ''Functional role of AhR in the expression of toxic effects by TCDD.''; Biochim Biophys Acta, 2003 PubMed Europe PMC Scholia
  34. Timsit YE, Negishi M; ''CAR and PXR: the xenobiotic-sensing receptors.''; Steroids, 2007 PubMed Europe PMC Scholia
  35. Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, Williams JD, Collins JL, Moore LB, Willson TM, Moore JT; ''A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer.''; Mol Cell, 2004 PubMed Europe PMC Scholia
  36. Gao H, Fält S, Sandelin A, Gustafsson JA, Dahlman-Wright K; ''Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver.''; Mol Endocrinol, 2008 PubMed Europe PMC Scholia
  37. Drocourt L, Ourlin JC, Pascussi JM, Maurel P, Vilarem MJ; ''Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes.''; J Biol Chem, 2002 PubMed Europe PMC Scholia
  38. Marchand A, Tomkiewicz C, Marchandeau JP, Boitier E, Barouki R, Garlatti M; ''2,3,7,8-Tetrachlorodibenzo-p-dioxin induces insulin-like growth factor binding protein-1 gene expression and counteracts the negative effect of insulin.''; Mol Pharmacol, 2005 PubMed Europe PMC Scholia
  39. Lindsey S, Papoutsakis ET; ''The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization.''; Br J Haematol, 2011 PubMed Europe PMC Scholia
  40. Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P, Vilarem MJ; ''The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors.''; Biochim Biophys Acta, 2003 PubMed Europe PMC Scholia
  41. Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T; ''The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR.''; Hepatology, 2001 PubMed Europe PMC Scholia
  42. Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT; ''The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
  43. Smoak KA, Cidlowski JA; ''Mechanisms of glucocorticoid receptor signaling during inflammation.''; Mech Ageing Dev, 2004 PubMed Europe PMC Scholia
  44. Rowlands JC, Gustafsson JA; ''Aryl hydrocarbon receptor-mediated signal transduction.''; Crit Rev Toxicol, 1997 PubMed Europe PMC Scholia
  45. Handschin C, Meyer UA; ''Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR.''; Arch Biochem Biophys, 2005 PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
117492view11:02, 21 May 2021EweitzModified title
89204view04:03, 23 August 2016AriuttaOntology Term : 'signaling pathway' added !
80688view15:22, 30 June 2015MkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABCB1GeneProductENSBTAG00000005997 (Ensembl)
  • ATP-binding cassette, sub-family B (MDR/TAP), member 1
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5243
ABCC2GeneProductATP-binding cassette, sub-family C (CFTR/MRP), member 2
ABCC3GeneProductATP-binding cassette, sub-family C (CFTR/MRP), member 3
ALAS1GeneProductENSBTAG00000004118 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000023330
CYP2A6GeneProductENSBTAG00000047815 (Ensembl)
  • cytochrome P450, family 2, subfamily A, polypeptide 6
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1548
CYP2B6GeneProductENSBTAG00000003871 (Ensembl)
  • cytochrome P450, family 2, subfamily B, polypeptide 6
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1555
CYP2C19GeneProductENSBTAG00000020375 (Ensembl)
  • cytochrome P450, family 2, subfamily C, polypeptide 19
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1557
CYP2C9GeneProductENSBTAG00000020375 (Ensembl)
  • cytochrome P450, family 2, subfamily C, polypeptide 9
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1559
CYP3A4GeneProductENSBTAG00000047379 (Ensembl)
  • cytochrome P450, family 3, subfamily A, polypeptide 4
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1576
CYP3A5GeneProductENSBTAG00000047379 (Ensembl)
  • cytochrome P450, family 3, subfamily A, polypeptide 5
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1577
CYP4A11GeneProductENSBTAG00000000229 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000187048
DNAJC7GeneProductENSBTAG00000002654 (Ensembl)
  • DnaJ (Hsp40) homolog, subfamily C, member 7
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7266
EHHADHGeneProductENSBTAG00000019625 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000113790
FOXO1GeneProductENSBTAG00000044105 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000150907
GSTA2GeneProductENSBTAG00000006546 (Ensembl)
  • glutathione S-transferase alpha 2
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2939
HSP90AA1GeneProductENSBTAG00000006270 (Ensembl)
  • heat shock protein 90kDa alpha (cytosolic), class A member 1
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3320
LigandMetaboliteCHEBI:77326 (ChEBI)
NCOA1GeneProductENSBTAG00000015007 (Ensembl)
  • nuclear receptor coactivator 1
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8648
NCOA2GeneProductENSBTAG00000020312 (Ensembl)
  • nuclear receptor coactivator 2
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10499
NCOA6GeneProductENSBTAG00000007930 (Ensembl)
  • nuclear receptor coactivator 6
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23054
NR1I3GeneProductENSBTAG00000009215 (Ensembl)
  • nuclear receptor subfamily 1, group I, member 3
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9970
PPARGC1AGeneProductENSBTAG00000017024 (Ensembl)
  • peroxisome proliferator-activated receptor gamma, coactivator 1 alpha
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10891
PPP2R4GeneProductENSBTAG00000001933 (Ensembl)
  • plays a role in translocation of CAR
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000119383
RXRAGeneProductENSBTAG00000017851 (Ensembl)
  • retinoid X receptor, alpha
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6256
SMC1AGeneProductENSBTAG00000017761 (Ensembl)
  • structural maintenance of chromosomes 1A
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8243
SP1GeneProductENSBTAG00000003021 (Ensembl)
  • Sp1 transcription factor
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
SULT1A1GeneProductENSBTAG00000008635 (Ensembl)
  • during fasting
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000196502
SULT2A1GeneProductENSBTAG00000039971 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105398
UGT1A1GeneProductENSBTAG00000026181 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000241635
UGT1A3GeneProductENSBTAG00000048275 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000243135
UGT1A4GeneProductENSBTAG00000048275 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000244474
UGT1A6GeneProduct
UGT1A9GeneProduct

Annotated Interactions

No annotated interactions
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