Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes

被引:353
作者
Maglich, JM [1 ]
Parks, DJ [1 ]
Moore, LB [1 ]
Collins, JL [1 ]
Goodwin, B [1 ]
Billin, AN [1 ]
Stoltz, CA [1 ]
Kliewer, SA [1 ]
Lambert, MH [1 ]
Willson, TM [1 ]
Moore, JT [1 ]
机构
[1] GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1074/jbc.M300138200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The orphan nuclear constitutive androstane receptor (CAR) is proposed to play a central role in the response to xenochemical stress. Identification of CAR target genes in humans has been limited by the lack of a selective CAR agonist. We report the identification of 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime (CITCO) as a novel human CAR agonist with the following characteristics: (a) potent activity in an in vitro fluorescence-based CAR activation assay; (b) selectivity for CAR over other nuclear receptors, including the xenobiotic pregnane X receptor (PXR); (c) the ability to induce human CAR nuclear translocation; and (d) the ability to induce the prototypical CAR target gene CYP2B6 in primary human hepatocytes. Using primary cultures of human hepatocytes, the effects of CITCO on gene expression were compared with those of the PXR ligand rifampicin. The relative expression of a number of genes encoding proteins involved in various aspects of steroid and xenobiotic metabolism was analyzed. Notably, CAR and PXR activators differentially regulated the expression of several genes, demonstrating that these two nuclear receptors subserve overlapping but distinct biological functions in human hepatocytes.
引用
收藏
页码:17277 / 17283
页数:7
相关论文
共 41 条
[1]   Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction [J].
Bertilsson, G ;
Heidrich, J ;
Svensson, K ;
Åsman, M ;
Jendeberg, L ;
Sydow-Bäckman, M ;
Ohlsson, R ;
Postlind, H ;
Blomquist, P ;
Berkenstam, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12208-12213
[2]   SXR, a novel steroid and xenobiotic-sensing nuclear receptor [J].
Blumberg, B ;
Sabbagh, W ;
Juguilon, H ;
Bolado, J ;
van Meter, CM ;
Ono, ES ;
Evans, RM .
GENES & DEVELOPMENT, 1998, 12 (20) :3195-3205
[3]  
Code EL, 1997, DRUG METAB DISPOS, V25, P985
[4]  
David G B, 1975, Prog Histochem Cytochem, V7, P1
[5]   Androstane metabolites bind to and deactivate the nuclear receptor CAR-β [J].
Forman, BM ;
Tzameli, I ;
Choi, HS ;
Chen, L ;
Simha, D ;
Seol, W ;
Evans, RM ;
Moore, DD .
NATURE, 1998, 395 (6702) :612-615
[6]   Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man [J].
Gibson, GG ;
Plant, NJ ;
Swales, KE ;
Ayrton, A ;
El-Sankary, W .
XENOBIOTICA, 2002, 32 (03) :165-206
[7]  
Goodwin B, 2001, MOL PHARMACOL, V60, P427
[8]   Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor [J].
Goodwin, B ;
Hodgson, E ;
D'Costa, DJ ;
Robertson, GR ;
Liddle, C .
MOLECULAR PHARMACOLOGY, 2002, 62 (02) :359-365
[9]   The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module [J].
Goodwin, B ;
Hodgson, E ;
Liddle, C .
MOLECULAR PHARMACOLOGY, 1999, 56 (06) :1329-1339
[10]   The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene [J].
Honkakoski, P ;
Zelko, I ;
Sueyoshi, T ;
Negishi, M .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (10) :5652-5658