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Regulation of P‐glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells
Author(s) -
Chan Gary N. Y.,
Hoque Md. Tozammel,
Cummins Carolyn L.,
Bendayan Reina
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07288.x
Subject(s) - pregnane x receptor , p glycoprotein , microvessel , pharmacology , receptor , nuclear receptor , constitutive androstane receptor , blood–brain barrier , biology , microbiology and biotechnology , endocrinology , biochemistry , cancer research , transcription factor , central nervous system , gene , multiple drug resistance , angiogenesis , antibiotics
J. Neurochem. (2011) 118 , 163–175. Abstract In mammalian systems, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been recognized as xenobiotic‐sensors which can up‐regulate the functional expression of drug transporters, such as P‐glycoprotein (P‐gp). In the brain, an increase in P‐gp expression can further limit drug permeability across the blood–brain barrier (BBB) and potentially reduce CNS pharmacotherapy efficacy. At present, the involvement of human PXR (hPXR) and CAR (hCAR) in the regulation of P‐gp expression at the human BBB is unknown. In this study, we investigate the role of hPXR and hCAR in the regulation of P‐gp expression using a human cerebral microvessel endothelial cell culture system. We demonstrate that activation of hPXR and hCAR by their respective ligands leads to P‐gp induction at both mRNA and protein levels, while pharmacological inhibitors of hPXR and hCAR prevent ligand‐mediated P‐gp induction. Ligand‐induced nuclear translocation of hPXR is observed, although such effect could not be demonstrated for hCAR. Furthermore, down‐regulation of hPXR and hCAR proteins using small‐interfering RNA decreased P‐gp expression. Our findings provide first evidence for P‐gp regulation by hPXR and hCAR at the human BBB and suggest insights on how to achieve selective P‐gp regulation at this site.