Identification of a Novel Human Constitutive Androstane Receptor (CAR) Agonist and Its Use in the Identification of CAR Target Genes

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][...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-05, Vol.278 (19), p.17277-17283
Main Authors: Maglich, Jodi M., Parks, Derek J., Moore, Linda B., Collins, Jon L., Goodwin, Bryan, Billin, Andrew N., Stoltz, Catherine A., Kliewer, Steven A., Lambert, Millard H., Willson, Timothy M., Moore, John T.
Format: Article
Language:English
Subjects:
Cells, Cultured
Gene Expression Regulation - drug effects
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Oximes - pharmacology
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - physiology
Signal Transduction - drug effects
Signal Transduction - genetics
Thiazoles - pharmacology
Transcription Factors - agonists
Transcription Factors - physiology
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Summary: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-carbaldehydeO-(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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M300138200