Title:
SCREENING SYSTEMS AND METHODS FOR IDENTIFYING MODULATORS OF XENOBIOTIC METABOLISM
Document Type and Number:
WIPO Patent Application WO2004034029
Kind Code:
A3
Abstract:
The present invention provides mice having reduced CAR receptor activity and mice expressing a human CAR receptor. These mice are useful in screening methods to identify CAR ligands, including compounds that modulate CAR receptor activity, compounds likely to have CAR-mediated toxicity, and analogs of these compounds with less potential toxicity.
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Inventors:
MOORE DAVID D (US)
WEI PING (US)
CHUA STEVEN S (US)
WEI PING (US)
CHUA STEVEN S (US)
Application Number:
PCT/US2003/032273
Publication Date:
November 04, 2004
Filing Date:
October 09, 2003
Export Citation:
Assignee:
BAYLOR COLLEGE MEDICINE (US)
MOORE DAVID D (US)
WEI PING (US)
CHUA STEVEN S (US)
MOORE DAVID D (US)
WEI PING (US)
CHUA STEVEN S (US)
International Classes:
A61K49/00; C07K14/72; C12N15/85; (IPC1-7): G01N33/00; A01K67/027
Other References:
MOORE L.B. ET AL: "Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands", J. OF BIOL. CHEM., vol. 275, no. 20, 19 May 2000 (2000-05-19), pages 15122 - 15127, XP000999376
ZHANG J. ET LA: "Modulation of Acetaminophen-Induced Hepatotoxicity by the Xenobiotic Receptor CAR", SCIENCE, vol. 298, 11 October 2002 (2002-10-11), pages 422 - 424, XP002981927
OLIVER J.D. ET AL: "Receptor-Mediated Hepatocarcinogenesis: Role of Hepatocyte Proliferation and Apoptosis", PHARMACOLOGY AND TOXICOLOGY, vol. 91, 2002, pages 1 - 7, XP002981928
XIE W. ET AL: "Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR", GENES AND DEVELOPMENT, vol. 14, 2000, pages 3014 - 3023, XP002959554
ROBERTSON G.R. ET AL: "Transgenic Mouse Models of Human CYP3A4 Gene Regulation", MOLECULAR PHARMACOLOGY, vol. 64, no. 1, 2003, pages 42 - 50, XP002981929
XIE W. ET AL: "Humanized xenobiotic response in mice expressing nuclear receptor SXR", NATURE, vol. 406, 27 July 2000 (2000-07-27), pages 435 - 439, XP002166094
XIE W. ET AL: "Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor", PNAS, vol. 100, no. 7, 1 April 2003 (2003-04-01), pages 4150 - 4155, XP002981930
HUANG W. ET AL: "Induction of bilirubin clearance by the constitutive androstane receptor (CAR)", PNAS, vol. 100, no. 7, 1 April 2003 (2003-04-01), pages 4156 - 4161, XP002981931
WEI P. ET AL: "The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism", NATURE, vol. 407, 19 October 2000 (2000-10-19), pages 920 - 923, XP000999432
ZHANG J. ET LA: "Modulation of Acetaminophen-Induced Hepatotoxicity by the Xenobiotic Receptor CAR", SCIENCE, vol. 298, 11 October 2002 (2002-10-11), pages 422 - 424, XP002981927
OLIVER J.D. ET AL: "Receptor-Mediated Hepatocarcinogenesis: Role of Hepatocyte Proliferation and Apoptosis", PHARMACOLOGY AND TOXICOLOGY, vol. 91, 2002, pages 1 - 7, XP002981928
XIE W. ET AL: "Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR", GENES AND DEVELOPMENT, vol. 14, 2000, pages 3014 - 3023, XP002959554
ROBERTSON G.R. ET AL: "Transgenic Mouse Models of Human CYP3A4 Gene Regulation", MOLECULAR PHARMACOLOGY, vol. 64, no. 1, 2003, pages 42 - 50, XP002981929
XIE W. ET AL: "Humanized xenobiotic response in mice expressing nuclear receptor SXR", NATURE, vol. 406, 27 July 2000 (2000-07-27), pages 435 - 439, XP002166094
XIE W. ET AL: "Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor", PNAS, vol. 100, no. 7, 1 April 2003 (2003-04-01), pages 4150 - 4155, XP002981930
HUANG W. ET AL: "Induction of bilirubin clearance by the constitutive androstane receptor (CAR)", PNAS, vol. 100, no. 7, 1 April 2003 (2003-04-01), pages 4156 - 4161, XP002981931
WEI P. ET AL: "The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism", NATURE, vol. 407, 19 October 2000 (2000-10-19), pages 920 - 923, XP000999432
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