CAR, driving into the future.

The nuclear orphan receptor CAR is active in the absence of ligand with the unique capability to be further regulated by activators. A number of these activators, including phenobarbital, do not directly bind to the receptor. Considered a xenobiotic sensing receptor, CAR transcriptionally modifies the expression of genes involved in the metabolism and elimination of xenobiotics and steroids in response to these compounds and other cellular metabolites. Its hepatic expression pattern endows the liver with the ability to protect against not only exogenous but also endogenous insults. The mechanism of CAR activation is complex, involving translocation from the cytoplasm to the nucleus in the presence of activators, followed by further activation steps in the nucleus. Although this mechanism remains under investigation, we have summarized here the cellular signaling pathways elucidated so far and speculate on the mechanism by which CAR activators regulate gene expression through this network.

[1]  S. Kliewer,et al.  Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity* , 2003, Journal of Biological Chemistry.

[2]  T. Sueyoshi,et al.  Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. , 2003, Molecular pharmacology.

[3]  T. Kawamoto,et al.  Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital , 2003, FEBS letters.

[4]  T. Willson,et al.  The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily. , 2003, Nucleic acids research.

[5]  R. Evans,et al.  Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. , 2003, Molecular endocrinology.

[6]  S. Auerbach,et al.  Alternatively spliced isoforms of the human constitutive androstane receptor. , 2003, Nucleic acids research.

[7]  T. Willson,et al.  The Drosophila Orphan Nuclear Receptor DHR38 Mediates an Atypical Ecdysteroid Signaling Pathway , 2003, Cell.

[8]  D. Concas,et al.  Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP. , 2003, Carcinogenesis.

[9]  R. Fletterick,et al.  Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. , 2003, Molecular cell.

[10]  Xiaohong Liu,et al.  Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors , 2003, Nature.

[11]  L. Moore,et al.  Identification of a Novel Human Constitutive Androstane Receptor (CAR) Agonist and Its Use in the Identification of CAR Target Genes* , 2003, The Journal of Biological Chemistry.

[12]  R. Tukey,et al.  Involvement of the Xenobiotic Response Element (XRE) in Ah Receptor-mediated Induction of Human UDP-glucuronosyltransferase 1A1 * , 2003, The Journal of Biological Chemistry.

[13]  E. Kanaya,et al.  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. , 2003, The Journal of biological chemistry.

[14]  D. Moore,et al.  Induction of bilirubin clearance by the constitutive androstane receptor (CAR) , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Wen Xie,et al.  Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  O. Gotoh,et al.  Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. , 2003, Molecular pharmacology.

[17]  C. Carlberg,et al.  The critical role of carboxy-terminal amino acids in ligand-dependent and -independent transactivation of the constitutive androstane receptor. , 2003, Molecular endocrinology.

[18]  T. Sueyoshi,et al.  Drug-activated nuclear receptors CAR and PXR , 2003, Annals of medicine.

[19]  S. Shoelson,et al.  Crystal Structure of the HNF4α Ligand Binding Domain in Complex with Endogenous Fatty Acid Ligand* , 2002, The Journal of Biological Chemistry.

[20]  D. Moore,et al.  Modulation of Acetaminophen-Induced Hepatotoxicity by the Xenobiotic Receptor CAR , 2002, Science.

[21]  Timothy M Willson,et al.  Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. , 2002, Structure.

[22]  V. Madison,et al.  Insights from a three-dimensional model into ligand binding to constitutive active receptor. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[23]  S. Kliewer,et al.  Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. , 2002, Molecular pharmacology.

[24]  B. M. Forman,et al.  A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity , 2002, Molecular and Cellular Biology.

[25]  K. Brouwer,et al.  Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbital. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[26]  J. Kemper,et al.  Glucocorticoid Receptor-interacting Protein 1 Mediates Ligand-independent Nuclear Translocation and Activation of Constitutive Androstane Receptor in Vivo * , 2002, The Journal of Biological Chemistry.

[27]  T. Sueyoshi,et al.  Residue threonine 350 confers steroid hormone responsiveness to the mouse nuclear orphan receptor CAR. , 2002, Molecular pharmacology.

[28]  C. Klaassen,et al.  Regulation of rat multidrug resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  Timothy M Willson,et al.  Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. , 2002, Molecular endocrinology.

[30]  E. R. Sánchez,et al.  A New First Step in Activation of Steroid Receptors , 2002, The Journal of Biological Chemistry.

[31]  D. Moras,et al.  Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. , 2002, Molecules and Cells.

[32]  Paul T Tarr,et al.  Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor* , 2002, The Journal of Biological Chemistry.

[33]  O. Fardel,et al.  Differential regulation of multidrug resistance-associated protein 2 (MRP2) and cytochromes P450 2B1/2 and 3A1/2 in phenobarbital-treated hepatocytes. , 2002, Biochemical pharmacology.

[34]  J. Pascussi,et al.  Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. , 2001, European journal of biochemistry.

[35]  L. Pedersen,et al.  Structure and function of sulfotransferases. , 2001, Archives of biochemistry and biophysics.

[36]  A. Sluder,et al.  A C. elegans orphan nuclear receptor contributes to xenobiotic resistance , 2001, Current Biology.

[37]  J. Sugatani,et al.  The phenobarbital response enhancer module in the human bilirubin UDP‐glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR , 2001, Hepatology.

[38]  T. Kawamoto,et al.  The Peptide Near the C Terminus Regulates Receptor CAR Nuclear Translocation Induced by Xenochemicals in Mouse Liver , 2001, Molecular and Cellular Biology.

[39]  L. Poellinger,et al.  The hsp90 Chaperone Complex Regulates Intracellular Localization of the Dioxin Receptor , 2001, Molecular and Cellular Biology.

[40]  I. Phillips,et al.  Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1. , 2001, The Biochemical journal.

[41]  L. Poellinger,et al.  The Immunophilin-like Protein XAP2 Regulates Ubiquitination and Subcellular Localization of the Dioxin Receptor* , 2000, The Journal of Biological Chemistry.

[42]  J. Pascussi,et al.  Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. , 2000, Molecular pharmacology.

[43]  C. Wolf,et al.  Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  T. Kawamoto,et al.  Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene. , 2000, Molecular endocrinology.

[45]  D. Moore,et al.  The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism , 2000, Nature.

[46]  C. Handschin,et al.  CXR, a chicken xenobiotic-sensing orphan nuclear receptor, is related to both mammalian pregnane X receptor (PXR) and constitutive androstane receptor (CAR). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[47]  B. Neuschwander‐Tetri,et al.  Humanized xenobiotic response in mice expressing nuclear receptor SXR , 2000, Nature.

[48]  R. Weinshilboum,et al.  Chapter 6: Estrogen Metabolism by Conjugation , 2000 .

[49]  L. Moore,et al.  Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands* , 2000, The Journal of Biological Chemistry.

[50]  E. Schuetz,et al.  The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[51]  B. Kemper,et al.  Tissue-specific chromatin structure of the phenobarbital-responsive unit and proximal promoter of CYP2B1/2 and modulation by phenobarbital. , 2000, Nucleic acids research.

[52]  A. Means,et al.  Activation of orphan receptor‐mediated transcription by Ca2+/calmodulin‐dependent protein kinase IV , 2000, The EMBO journal.

[53]  L. Corcos,et al.  Regulation of phenobarbital induction of the cytochrome P450 2b9/10 genes in primary mouse hepatocyte culture. Involvement of calcium- and cAMP-dependent pathways. , 2000, European journal of biochemistry.

[54]  T. Kawamoto,et al.  Phenobarbital-Responsive Nuclear Translocation of the Receptor CAR in Induction of the CYP2B Gene , 1999, Molecular and Cellular Biology.

[55]  J. Barsony,et al.  Hormone-dependent Translocation of Vitamin D Receptors Is Linked to Transactivation* , 1999, The Journal of Biological Chemistry.

[56]  K. Umesono,et al.  A Unified Nomenclature System for the Nuclear Receptor Superfamily , 1999, Cell.

[57]  Paavo Honkakoski,et al.  The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene* , 1999, The Journal of Biological Chemistry.

[58]  W. Sabbagh,et al.  SXR, a novel steroid and xenobiotic-sensing nuclear receptor. , 1998, Genes & development.

[59]  David D. Moore,et al.  Androstane metabolites bind to and deactivate the nuclear receptor CAR-β , 1998, Nature.

[60]  T. Sueyoshi,et al.  The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene , 1998, Molecular and Cellular Biology.

[61]  H. S. Choi,et al.  Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. , 1998, Molecular endocrinology.

[62]  K. Umesono,et al.  BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. , 1998, Genes & development.

[63]  M. Negishi,et al.  Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene. , 1998, Molecular pharmacology.

[64]  J. Lehmann,et al.  An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway , 1998, Cell.

[65]  D. Moore,et al.  Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR* , 1997, The Journal of Biological Chemistry.

[66]  I. M. Marks,et al.  The amino-terminal transforming region of simian virus 40 large T and small t antigens functions as a J domain , 1997, Molecular and cellular biology.

[67]  T. Darden,et al.  Structural flexibility and functional versatility of mammalian P450 enzymes , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[68]  M. Negishi,et al.  Characterization of Phenobarbital-inducible Mouse Cyp2b10 Gene Transcription in Primary Hepatocytes (*) , 1996, The Journal of Biological Chemistry.

[69]  C. Thummel,et al.  Isolation, regulation, and DNA-binding properties of three Drosophila nuclear hormone receptor superfamily members. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[70]  B. Burchell,et al.  Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronosyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. , 1994, The Biochemical journal.

[71]  R. Pollenz,et al.  The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. , 1994, Molecular pharmacology.

[72]  D. Moore,et al.  A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements , 1994, Molecular and cellular biology.

[73]  L. Corcos,et al.  The phenobarbital-induced transcriptional activation of cytochrome P-450 genes is blocked by the glucocorticoid-progesterone antagonist RU486. , 1993, Molecular pharmacology.

[74]  S. Langouet,et al.  Preferential increase of glutathione S-transferase class alpha transcripts in cultured human hepatocytes by phenobarbital, 3-methylcholanthrene, and dithiolethiones. , 1993, Cancer research.

[75]  R. Lindberg,et al.  Alteration of mouse cytochrome P450coh substrate specificity by mutation of a single amino-acid residue , 1989, Nature.

[76]  N. Musto,et al.  Fluctuations in plasma testosterone levels in adult male rats and mice. , 1973, Endocrinology.

[77]  D. Tremethick,et al.  Evidence that the coactivator CBP/p300 is important for phenobarbital-induced but not basal expression of the CYP2H1 gene. , 2003, Molecular pharmacology.

[78]  T. Kawamoto,et al.  The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity. , 2003, Archives of biochemistry and biophysics.

[79]  J. Pascussi,et al.  Transcriptional analysis of the orphan nuclear receptor constitutive androstane receptor (NR1I3) gene promoter: identification of a distal glucocorticoid response element. , 2003, Molecular endocrinology.

[80]  W. Charman,et al.  The Mucosa of the Small Intestine , 2002, Clinical pharmacokinetics.

[81]  D. Moore,et al.  Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response , 2002, The Pharmacogenomics Journal.

[82]  J. Pascussi,et al.  Direct expression of fluorescent protein-tagged nuclear receptor CAR in mouse liver. , 2002, Methods in enzymology.

[83]  C. Carlberg,et al.  Orphan nuclear receptor binding site in the human inducible nitric oxide synthase promoter mediates responsiveness to steroid and xenobiotic ligands , 2002, Journal of cellular biochemistry.

[84]  J. Lehmann,et al.  Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. , 2002, Molecular pharmacology.

[85]  T. Sueyoshi,et al.  Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. , 2001, Annual review of pharmacology and toxicology.

[86]  R. Tukey,et al.  Human UDP-glucuronosyltransferases: metabolism, expression, and disease. , 2000, Annual review of pharmacology and toxicology.

[87]  M. Negishi,et al.  Regulatory DNA elements of phenobarbital‐responsive cytochrome P450 CYP2B genes , 1998, Journal of biochemical and molecular toxicology.

[88]  J. Hayes,et al.  The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. , 1995, Critical reviews in biochemistry and molecular biology.

[89]  D. Bicknell,et al.  The development and application of a radioimmunoassay for 5α-androst-16-en-3α-ol in plasma , 1976 .