{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe nuclear receptor NR1I3, commonly known as the constitutive androstane receptor (CAR), is a central regulator of hepatic xenobiotic metabolism. It mediates the induction of numerous detoxification genes, including those involved in bilirubin clearance and the metabolism of drugs such as acetaminophen, thereby contributing to hepatoprotection and, in certain cases, to the treatment of hyperbilirubinemia (e.g., neonatal jaundice). CAR’s activation in liver cells promotes the coordinated expression of phase I drug‐metabolizing cytochrome P450 enzymes and phase II conjugating enzymes, establishing a first‐line response to xenobiotic stress (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCAR exerts its effects in part by regulating the transcription of cytochrome P450 enzymes. It directly transactivates genes such as CYP3A4, CYP3A5, CYP2C9, and CYP2C8 by binding to specific response elements within their promoters, thereby facilitating the hepatic clearance and biotransformation of a wide array of xenobiotics and endogenous substrates (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in drug metabolism, CAR activity is modulated by inflammatory and stress‐related signals. During inflammatory states, for example, cytokines such as interleukin‐1β down‐regulate CAR expression, thereby impairing the induction of key drug–metabolizing enzymes and transporters. Moreover, endobiotic signals, including those activated by natural compounds from herbal extracts, can influence CAR‐mediated responses (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinical and pharmacogenomic studies have explored the impact of genetic variability in NR1I3 on drug disposition and adverse drug reactions. Investigations into single‐nucleotide polymorphisms within CAR have aimed to assess their relationship with altered drug clearance and toxicity—findings that may ultimately inform individualized therapeutic strategies (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical function in xenobiotic detoxification, CAR is also implicated in the regulation of hepatic energy metabolism, liver growth, and even tumorigenesis. Its chronic activation can contribute to liver hypertrophy and carcinogenesis by modulating proliferative and apoptotic pathways (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCAR activity is tightly coordinated by an array of post‐translational modifications and transcriptional mechanisms. Alternative splicing generates receptor isoforms with distinct activities, while interactions with coactivators—such as PGC‑1α and HNF4α—as well as reversible phosphorylation (notably at threonine residues) regulate its nuclear translocation and DNA binding capacity. These molecular events ensure the precise control of downstream gene expression in response to both exogenous and endogenous signals (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSpecies‐specific differences in ligand recognition have also been documented for CAR. For instance, the antiemetic meclizine functions as an agonist for murine CAR yet acts as an inverse agonist for its human counterpart, underscoring the importance of considering interspecies variations in CAR‐mediated responses (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCAR’s diverse regulatory functions are further enriched through cross-talk with other nuclear receptors and signaling pathways. It can antagonize estrogen receptor–mediated transcription by sequestering limiting amounts of shared coactivators, and it interferes with other transcription factors to regulate the expression of key transporters such as MRP4 and P‑glycoprotein. Such interactions contribute to multidrug resistance phenomena observed in cancer and affect drug penetration across critical barriers (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCooperative interactions between CAR and other transcription factors, such as ATF5, further amplify its ability to stimulate the expression of drug–metabolizing enzymes in hepatocytes, reinforcing the maintenance of liver homeostasis (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUpstream, CAR is subjected to multifaceted regulation by environmental and hormonal cues. Networks involving microRNAs (notably miR‑122), early growth response proteins (EGR1), and PPARα signaling converge on CAR to finely tune its expression and activation status, thereby linking xenobiotic sensing to broader metabolic and developmental pathways (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn specialized tissues, such as the testis, CAR also plays a role in regulating drug transporter expression at the blood–testis barrier, which may impact the distribution and efficacy of therapeutics like antiretroviral agents (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent genome–wide transcriptomic analyses have broadened our understanding of CAR’s transcriptional repertoire. Such studies elucidate how CAR integrates into global metabolic networks and highlight its involvement in both normal physiology and disease processes (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jun Zhang, Wendong Huang, Steven S Chua, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1073502"}], "href": "https://doi.org/10.1126/science.1073502"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12376703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12376703"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wen Xie, Mei-Fei Yeuh, Anna Radominska-Pandya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0438010100"}], "href": "https://doi.org/10.1073/pnas.0438010100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12644700"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12644700"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Wendong Huang, Jun Zhang, Steven S Chua, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of bilirubin clearance by the constitutive androstane receptor (CAR)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0630614100"}], "href": "https://doi.org/10.1073/pnas.0630614100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12644704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12644704"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Wendong Huang, Jun Zhang, Michele Washington, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2004-0520"}], "href": "https://doi.org/10.1210/me.2004-0520"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15831521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15831521"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Bryan Goodwin, Ecushla Hodgson, Daniel J D'Costa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.62.2.359"}], "href": "https://doi.org/10.1124/mol.62.2.359"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12130689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12130689"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Stephen S Ferguson, Edward L LeCluyse, Masahiko Negishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.62.3.737"}], "href": "https://doi.org/10.1124/mol.62.3.737"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12181452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12181452"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Oliver Burk, Ina Koch, Judy Raucy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M404949200"}], "href": "https://doi.org/10.1074/jbc.M404949200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15252010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15252010"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Stephen S Ferguson, Yuping Chen, Edward L LeCluyse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.105.013169"}], "href": "https://doi.org/10.1124/mol.105.013169"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15933212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15933212"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Eric Assenat, Sabine Gerbal-Chaloin, Dominique Larrey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.20387"}], "href": "https://doi.org/10.1002/hep.20387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15382119"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15382119"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Linhao Li, Joseph D Stanton, Antonia H Tolson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharm Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11095-008-9788-8"}], "href": "https://doi.org/10.1007/s11095-008-9788-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19034627"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19034627"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kazuma Kiyotani, Taisei Mushiroda, Michiaki Kubo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1349-7006.2008.00765.x"}], "href": "https://doi.org/10.1111/j.1349-7006.2008.00765.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18294295"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18294295"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Christoph Wyen, Heidy Hendra, Marco Siccardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Antimicrob Chemother (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jac/dkr272"}], "href": "https://doi.org/10.1093/jac/dkr272"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21715435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21715435"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Claudia P Cortes, Marco Siccardi, Ammara Chaikan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Correlates of efavirenz exposure in Chilean patients affected with human immunodeficiency virus reveals a novel association with a polymorphism in the constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ther Drug Monit (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/FTD.0b013e318274197e"}], "href": "https://doi.org/10.1097/FTD.0b013e318274197e"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23172109"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23172109"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Matthew Wortham, Maciej Czerwinski, Lin He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Metab Dispos (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/dmd.107.016436"}], "href": "https://doi.org/10.1124/dmd.107.016436"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17576804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17576804"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Yoshihiro Konno, Masahiko Negishi, Susumu Kodama "}, {"type": "b", "children": [{"type": "t", "text": "The roles of nuclear receptors CAR and PXR in hepatic energy metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Metab Pharmacokinet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2133/dmpk.23.8"}], "href": "https://doi.org/10.2133/dmpk.23.8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18305370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18305370"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jean Marc Pascussi, Maryvonne Busson-Le Coniat, Patrick Maurel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional analysis of the orphan nuclear receptor constitutive androstane receptor (NR1I3) gene promoter: identification of a distal glucocorticoid response element."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2002-0244"}], "href": "https://doi.org/10.1210/me.2002-0244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12511605"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12511605"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Takuma Shiraki, Noriko Sakai, Eiko Kanaya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M212859200"}], "href": "https://doi.org/10.1074/jbc.M212859200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12551939"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12551939"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Scott S Auerbach, Richard Ramsden, Matthew A Stoner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alternatively spliced isoforms of the human constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkg419"}], "href": "https://doi.org/10.1093/nar/gkg419"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12799447"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12799447"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Yuping Chen, Grace Kissling, Masahiko Negishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Exp Ther (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/jpet.105.087072"}], "href": "https://doi.org/10.1124/jpet.105.087072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15919766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15919766"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Xinrong Chen, Jimei Zhang, Sharon M Baker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Toxicology (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tox.2006.12.019"}], "href": "https://doi.org/10.1016/j.tox.2006.12.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17276571"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17276571"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Shingo Mutoh, Makoto Osabe, Kaoru Inoue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.048108"}], "href": "https://doi.org/10.1074/jbc.M109.048108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19858220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19858220"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Wendong Huang, Jun Zhang, Ping Wei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2004-0046"}], "href": "https://doi.org/10.1210/me.2004-0046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15272053"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15272053"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Gyesik Min, Hwajin Kim, Yangjin Bae, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M205239200"}], "href": "https://doi.org/10.1074/jbc.M205239200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12114525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12114525"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Barbara Renga, Marco Migliorati, Andrea Mencarelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Farnesoid X receptor suppresses constitutive androstane receptor activity at the multidrug resistance protein-4 promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbagrm.2011.01.008"}], "href": "https://doi.org/10.1016/j.bbagrm.2011.01.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21296199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21296199"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Gary N Y Chan, Md Tozammel Hoque, Carolyn L Cummins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2011.07288.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2011.07288.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21517853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21517853"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "A A Takwi, Y-M Wang, J Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2013.330"}], "href": "https://doi.org/10.1038/onc.2013.330"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23934188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23934188"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Maya Pascual, M José Gómez-Lechón, José V Castell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ATF5 is a highly abundant liver-enriched transcription factor that cooperates with constitutive androstane receptor in the transactivation of CYP2B6: implications in hepatic stress responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Metab Dispos (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/dmd.107.019380"}], "href": "https://doi.org/10.1124/dmd.107.019380"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18332083"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18332083"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Lu Zhang, Xiaoqiao Liu, Xuegong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of important long non-coding RNAs and highly recurrent aberrant alternative splicing events in hepatocellular carcinoma through integrative analysis of multiple RNA-Seq datasets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Genomics (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00438-015-1163-y"}], "href": "https://doi.org/10.1007/s00438-015-1163-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26711644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26711644"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Jatinder K Lamba "}, {"type": "b", "children": [{"type": "t", "text": "Pharmacogenetics of the constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenomics (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2217/14622416.9.1.71"}], "href": "https://doi.org/10.2217/14622416.9.1.71"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18154449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18154449"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Kaoru Inoue, Masahiko Negishi "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear receptor CAR requires early growth response 1 to activate the human cytochrome P450 2B6 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M800729200"}], "href": "https://doi.org/10.1074/jbc.M800729200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18303024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18303024"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Marta Benet, Agustín Lahoz, Carla Guzmán, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CCAAT/enhancer-binding protein alpha (C/EBPalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene: application to the development of a metabolically competent human hepatic cell model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.118364"}], "href": "https://doi.org/10.1074/jbc.M110.118364"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20622021"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20622021"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Ryota Shizu, Sawako Shindo, Takemi Yoshida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0041291"}], "href": "https://doi.org/10.1371/journal.pone.0041291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22815988"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22815988"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Sana-Kay Whyte-Allman, Md Tozammel Hoque, Mohammad-Ali Jenabian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Exp Ther (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/jpet.117.243584"}], "href": "https://doi.org/10.1124/jpet.117.243584"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28970358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28970358"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Benjamin A Kandel, Maria Thomas, Stefan Winter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbagrm.2016.03.007"}], "href": "https://doi.org/10.1016/j.bbagrm.2016.03.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26994748"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26994748"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of CAR and PXR Expression in Health and Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells9112395"}], "href": "https://doi.org/10.3390/cells9112395"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33142929"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33142929"}]}]}]}