Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor

被引:210
作者
Goodwin, B
Hodgson, E
D'Costa, DJ
Robertson, GR
Liddle, C
机构
[1] Univ Sydney, Westmead Millennium Inst, Dept Clin Pharmacol, Westmead, NSW 2145, Australia
[2] Univ Sydney, Westmead Millennium Inst, Storr Liver Unit, Westmead, NSW 2145, Australia
关键词
D O I
10.1124/mol.62.2.359
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in adult human liver, is both constitutively expressed and transcriptionally activated by a variety of structurally diverse xenochemicals. In this study, we examined the role of the constitutive androstane receptor (CAR), a member of the steroid/retinoid/ thyroid hormone receptor superfamily, in the transcriptional regulation of CYP3A4. Herein, we demonstrate that CAR is capable of trans-activating expression of the CYP3A4 gene, both in vitro and in vivo. Induction of CYP3A4 is dependent on cooperativity between elements within the promoter proximal region of the gene and the distal xenobiotic-responsive enhancer module. CAR responsiveness was shown to be primarily mediated by two high-affinity binding motifs located within the CYP3A4 gene 5'-flanking region, approximately 7720 and 150 bases upstream of the transcription initiation site. Importantly, the human CAR response elements also mediate trans-activation of CYP3A4 by the human pregnane X receptor, suggesting that interplay between these receptors is likely to be an important determinant of CYP3A4 expression.
引用
收藏
页码:359 / 365
页数:7
相关论文
共 32 条
[1]  
[Anonymous], 1994, MANIPULATING MOUSE E
[2]   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
[3]   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
[4]  
Chang TKH, 1997, CANCER RES, V57, P1946
[5]   XENOBIOTIC-INDUCIBLE TRANSCRIPTION OF CYTOCHROME-P450 GENES [J].
DENISON, MS ;
WHITLOCK, JP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (31) :18175-18178
[6]   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
[7]  
FOSTER R, 1988, J BIOL CHEM, V263, P11528
[8]   Human CYP2B6: expression, inducibility and catalytic activities [J].
Gervot, L ;
Rochat, B ;
Gautier, JC ;
Bohnenstengel, F ;
Kroemer, H ;
de Berardinis, V ;
Martin, H ;
Beaune, P ;
de Waziers, I .
PHARMACOGENETICS, 1999, 9 (03) :295-306
[9]  
Goodwin B, 2001, MOL PHARMACOL, V60, P427
[10]   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