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Sci Rep. 2015 May 20;5:10405. doi: 10.1038/srep10405.

Quantitative high-throughput identification of drugs as modulators of human constitutive androstane receptor.

Author information

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, 21201 Maryland.
National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, 20892 Maryland.
Bioreclamation IVT, Baltimore, 20 Maryland.


The constitutive androstane receptor (CAR, NR1I3) plays a key role in governing the transcription of numerous hepatic genes that involve xenobiotic metabolism/clearance, energy homeostasis, and cell proliferation. Thus, identification of novel human CAR (hCAR) modulators may not only enhance early prediction of drug-drug interactions but also offer potentially novel therapeutics for diseases such as metabolic disorders and cancer. In this study, we have generated a double stable cell line expressing both hCAR and a CYP2B6-driven luciferase reporter for quantitative high-throughput screening (qHTS) of hCAR modulators. Approximately 2800 compounds from the NIH Chemical Genomics Center Pharmaceutical Collection were screened employing both the activation and deactivation modes of the qHTS. Activators (115) and deactivators (152) of hCAR were identified from the primary qHTS, among which 10 agonists and 10 antagonists were further validated in the physiologically relevant human primary hepatocytes for compound-mediated hCAR nuclear translocation and target gene expression. Collectively, our results reveal that hCAR modulators can be efficiently identified through this newly established qHTS assay. Profiling drug collections for hCAR activity would facilitate the prediction of metabolism-based drug-drug interactions, and may lead to the identification of potential novel therapeutics.

[Indexed for MEDLINE]
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