title: The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity.
abstract: The nuclear receptor CAR (constitutive active receptor) mediates the induction of transcription of cytochrome P450 (CYP) genes by phenobarbital (PB) and PB-type inducers. A recent study using CAR-null mice has shown that CAR regulates not only the CYP genes but also other genes encoding various drug/steroid-metabolizing enzymes. In addition to coordinating these enzymes, CAR plays other roles in hepatic gene expression: CAR represses various genes including carnitine palmitoyltransferase 1a and phosphoenolpyruvate carboxykinase 1 in response to PB, and the receptor regulates the constitutive expression of genes such as squalene epoxidase. On the other hand, induction of certain genes such as amino levulinate synthase 1 by PB is not regulated by CAR. Here we describe diverse roles of CAR in hepatic gene expression with a particular focus on endogenous substances such as cholesterol, bilirubin, and steroid hormones.
authors.affiliation: Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010105:Oxygenases / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology*; D050603:Squalene Monooxygenase; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: D000090702:Constitutive Androstane Receptor; D004967:Estrogens; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002784:Cholesterol; D010105:Oxygenases; D050603:Squalene Monooxygenase; D002334:Carnitine O-Palmitoyltransferase; D000624:5-Aminolevulinate Synthetase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D002118:Calcium