An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids

被引:639
作者
Xie, W
Radominska-Pandya, A
Shi, YH
Simon, CM
Nelson, MC
Ong, ES
Waxman, DJ
Evans, RM
机构
[1] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA
[2] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA
[3] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA
[4] Boston Univ, Div Cell & Mol Biol, Dept Biol, Boston, MA 02215 USA
关键词
D O I
10.1073/pnas.051014398
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hepatic hydroxylation is an essential step in the metabolism and excretion of bile acids and is necessary to avoid pathologic conditions such as cholestasis and liver damage. In this report, we demonstrate that the human xenobiotic receptor SXR (steroid and xenobiotic receptor) and its rodent homolog PXR (pregnane X receptor) serve as functional bile acid receptors in both cultured cells and animals. In particular, the secondary bile acid derivative lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a metabolic substrate far CYP3A hydroxylation. By using combinations of knockout and transgenic animals, we show that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazolamine. Therefore, we establish SXR and PXR as bile acid receptors and a role for the xenobiotic response in the detoxification of bile acids.
引用
收藏
页码:3375 / 3380
页数:6
相关论文
共 30 条
[21]   HORMONES AND RESISTANCE [J].
SELYE, H .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1971, 60 (01) :1-&
[22]   Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis [J].
Sinal, CJ ;
Tohkin, M ;
Miyata, M ;
Ward, JM ;
Lambert, G ;
Gonzalez, FJ .
CELL, 2000, 102 (06) :731-744
[23]  
TAYLOR W, 1997, BRIT J PHARMACOL, V61, P133
[24]   PATHOGENESIS OF LITHOCHOLATE-INDUCED INTRAHEPATIC CHOLESTASIS - ROLE OF GLUCURONIDATION AND HYDROXYLATION OF LITHOCHOLATE [J].
VU, DD ;
TUCHWEBER, B ;
PLAA, GL ;
YOUSEF, IM .
BIOCHIMICA ET BIOPHYSICA ACTA, 1992, 1126 (01) :53-59
[25]   Endogenous bile acids are ligands for the nuclear receptor FXR BAR [J].
Wang, HB ;
Chen, J ;
Hollister, K ;
Sowers, LC ;
Forman, BM .
MOLECULAR CELL, 1999, 3 (05) :543-553
[26]   P450 gene induction by structurally diverse xenochemicals: Central role of nuclear receptors CAR, PXR, and PPAR [J].
Waxman, DJ .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1999, 369 (01) :11-23
[27]   Stimulation of bile acid 6 alpha-hydroxylation by rifampin [J].
Wietholtz, H ;
Marschall, HU ;
Sjovall, J ;
Matern, S .
JOURNAL OF HEPATOLOGY, 1996, 24 (06) :713-718
[28]   Humanized xenobiotic response in mice expressing nuclear receptor SXR [J].
Xie, W ;
Barwick, JL ;
Downes, M ;
Blumberg, B ;
Simon, CM ;
Nelson, MC ;
Neuschwander-Tetri, BA ;
Bruntk, EM ;
Guzelian, PS ;
Evans, RM .
NATURE, 2000, 406 (6794) :435-439
[29]   Reciprocal activation of Xenobiotic response genes by nuclear receptors SXR/PXR and CAR [J].
Xie, W ;
Barwick, JL ;
Simon, CM ;
Pierce, AM ;
Safe, S ;
Blumberg, B ;
Guzelian, PS ;
Evans, RM .
GENES & DEVELOPMENT, 2000, 14 (23) :3014-3023
[30]  
ZIMNIAK P, 1988, J LIPID RES, V29, P183