Retinoic acids repress constitutive active receptor-mediated induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene of the CYP2B10 gene in mouse primary hepatocytes.
The nuclear orphan receptor constitutive active receptor (CAR) can be activated to induce CYP2B genes by the potent phenobarbital-type inducer 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in which the receptor forms a heterodimer with the retinoid X receptor (RXR) and binds to a conserved enhancer element NR1. Effects of retinoic acids on the activation of CAR were examined. Treatment with 9-cis- or all-trans-retinoic acid markedly repressed TCPOBOP induction of CYP2B10 mRNA in mouse primary hepatocytes. Both retinoic acids also repressed TCPOBOP-induced NR1 enhancer activity in both transfected hepatocytes and HepG2 cells. Moreover, coexpression of the retinoic acid receptor (RAR) increased the repression in the cotransfected HepG2 cells, whereas that of RXR decreased the repression. Thus, the increased heterodimerization of RXR with RAR by retinoic acid treatment seemed to reduce the RXR available for CAR heterodimerization, resulting in the repression of CAR activity. This type of nuclear receptor signaling may play an important role as a modulator in the CYP2B regulation.
Kakizaki
Satoru
S
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. kakizaki@niehs.nih.gov
Karami
Sohrab
S
Negishi
Masahiko
M
D000077556:Alitretinoin; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D004794:Enzyme Repression / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000502:physiology; D013250:Steroid Hydroxylases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2