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Title: Differential effect of meclizine on the activity of human pregnane X receptor and constitutive androstane receptor
Authors: Lau, A.J 
Yang, G
Rajaraman, G
Baucom, C.C
Chang, T.K.H
Keywords: constitutive androstane receptor
cytochrome P450 3A4
pregnane X receptor
steroid receptor coactivator 1
animal experiment
cell based reporter gene assay
cell strain HepG2
controlled study
drug antagonism
drug effect
drug receptor binding
fluorescence resonance energy transfer
gene expression
genetic transfection
human cell
ligand binding
liver cell
nucleotide sequence
priority journal
Cells, Cultured
Dose-Response Relationship, Drug
Hep G2 Cells
Protein Binding
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid
Issue Date: 2011
Publisher: American Society for Pharmacology and Experimental Therapeutics
Citation: Lau, A.J, Yang, G, Rajaraman, G, Baucom, C.C, Chang, T.K.H (2011). Differential effect of meclizine on the activity of human pregnane X receptor and constitutive androstane receptor. Journal of Pharmacology and Experimental Therapeutics 336 (3) : 816-826. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Conflicting data exist as to whether meclizine is an activator of human pregnane X receptor (hPXR). Therefore, we conducted a detailed, systematic investigation to determine whether meclizine affects hPXR activity by performing a cell-based reporter gene assay, a time-resolved fluorescence resonance energy transfer competitive ligand-binding assay, a mammalian twohybrid assay to assess coactivator recruitment, and a hPXR target gene expression assay. In pregnane X receptor (PXR)-transfected HepG2 cells, meclizine activated hPXR to a greater extent than rat PXR. It bound to hPXR ligand-binding domain and recruited steroid receptor coactivator-1 to the receptor. Consistent with its hPXR agonism, meclizine increased hPXR target gene expression (CYP3A4) in human hepatocytes. However, it did not increase but decreased testosterone 6?-hydroxylation, suggesting inhibition of CYP3A catalytic activity. Meclizine has also been reported to be an inverse agonist and antagonist of human constitutive androstane receptor (hCAR). Therefore, given that certain tissues (e.g., liver) express both hPXR and hCAR and that various genes are cross-regulated by them, we quantified the expression of a hCAR- and hPXR-regulated gene (CYP2B6) in cultured human hepatocytes treated with meclizine. This drug did not decrease constitutive CYP2B6 mRNA expression or attenuate hCAR agonist-mediated increase in CYP2B6 mRNA and CYP2B6-catalyzed bupropion hydroxylation levels. These observations reflect hPXR agonism and the lack of hCAR inverse agonism and antagonism by meclizine, which were assessed by a hCAR reporter gene assay and mammalian two-hybrid assay. In conclusion, meclizine is a hPXR agonist, and it does not act as a hCAR inverse agonist or antagonist in cultured human hepatocytes. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.
Source Title: Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
DOI: 10.1124/jpet.110.175927
Rights: Attribution 4.0 International
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