Pharmaceutical use of mouse models humanized for the xenobiotic receptor

被引：55

作者：

Xie, W ^{[1
]}

Evans, RM ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Gene Express Lab, Howard Hughes Med Inst, La Jolla, CA 92037 USA

来源：

DRUG DISCOVERY TODAY | 2002年 / 7卷 / 09期

关键词：

D O I：

10.1016/S1359-6446(02)02251-1

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The regulation of hepatic cytochrome P450 (CYP) enzymes is implicated in both drug metabolism and drug-drug interactions. The CYP genes are induced by numerous xenobiotics, yet the inducibility shows clear species specificity. Recently, the rodent nuclear receptor PXR and its human homolog, SXR or hPXR, have been established as species-specific xenosensors that regulate CYP3A enzymes. By knocking-out the rodent gene and replacing it with the human receptor, a 'humanized' mouse model has been established. Displaying a human drug-response profile, this mouse represents a unique tool to dissect the drug-induced xenobiotic response and should aid the development of safer drugs.

引用

页码：509 / 515

页数：7

共 41 条

[1]

Barwick JL, 1996, MOL PHARMACOL, V50, P10

[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] BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites [J].

Blumberg, B ;

Kang, HJ ;

Bolado, J ;

Chen, HW ;

Craig, AG ;

Moreno, TA ;

Umesono, K ;

Perlmann, T ;

De Robertis, EM ;

Evans, RM .

GENES & DEVELOPMENT, 1998, 12 (09) :1269-1277

[5] Orphan nuclear receptors - new ligands and new possibilities [J].

Blumberg, B ;

Evans, RM .

GENES & DEVELOPMENT, 1998, 12 (20) :3149-3155

[6]

BOCHERDING SM, 1992, ARCH INTERN MED, V152, P711

[7] Nuclear receptors and lipid physiology: Opening the X-files [J].

Chawla, A ;

Repa, JJ ;

Evans, RM ;

Mangelsdorf, DJ .

SCIENCE, 2001, 294 (5548) :1866-1870

[8] XENOBIOTIC-INDUCIBLE TRANSCRIPTION OF CYTOCHROME-P450 GENES [J].

DENISON, MS ;

WHITLOCK, JP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (31) :18175-18178

[9] Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR [J].

Dussault, I ;

Lin, M ;

Hollister, K ;

Wang, EH ;

Synold, TW ;

Forman, BM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (36) :33309-33312

[10] 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

← 1 2 3 4 5 →