The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity.
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.
Yamamoto
Yukio
Y
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Kawamoto
Takeshi
T
Negishi
Masahiko
M
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
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