Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR.
Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key regulators of drug-metabolizing enzymes and transporters. These two receptors are closely associated with each other and also have overlapping functions. This study investigated the overall hepatic gene expression profiles and the regulatory roles of these nuclear receptors using CAR/PXR single and double knockout mice. Basal and ligand-stimulated gene expression profiles were obtained in each mouse using cDNA microarrays and a reverse transcriptase-polymerase chain reaction. Enzymes such as Cyp2b10, Cyp3a11, Cdc20 and Cdk1 displayed both CAR- and PXR-dependent induction. Inversely, enzymes such as Cyp4a10, Fos and Mme displayed both CAR- and PXR-dependent repression. Enzymes such as Cyp1a1, Cyp1a2 and c-Myc represented the group of genes only induced by CAR. Enzymes such as Aacs represented the group of genes induced only by the PXR. CAR and PXR are closely associated and have diverse roles, both as positive and negative regulators of hepatic genes including xenobiotic metabolism, apoptosis, cholesterol biosynthesis, lipid metabolism, and cytokine signaling pathways.
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Hiroki
H
Tojima
Satoru
S
Kakizaki
Yuichi
Y
Yamazaki
Daichi
D
Takizawa
Norio
N
Horiguchi
Ken
K
Sato
Masatomo
M
Mori
D000818:Animals; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077297:Pregnane X Receptor; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003577:Cytochrome P-450 Enzyme System