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J. Biol. Chem., Vol. 278, Issue 19, 17277-17283, May 9, 2003
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From Nuclear Receptor Discovery Research, GlaxoSmithKline,
Research Triangle Park, North Carolina 27709
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-carbaldehyde O-(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.
Identification of a Novel Human Constitutive
Androstane Receptor (CAR) Agonist and Its Use in the Identification of
CAR Target Genes*
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: GlaxoSmithKline, 5 Moore Dr., V-116B, Research Triangle Park, NC 27709. Tel.: 919-483-3936; Fax: 919-315-6720; E-mail: john.t.moore@gsk.com.
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