Journal
JOURNAL OF NEUROCHEMISTRY
Volume 118, Issue 2, Pages 163-175Publisher
WILEY
DOI: 10.1111/j.1471-4159.2011.07288.x
Keywords
blood-brain barrier; constitutive androstane receptor; human brain microvessel endothelial cells; orphan nuclear receptor; P-glycoprotein; pregnane X receptor
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP56976]
- Ontario HIV Treatment Network Ministry of Health of Ontario
- NSERC (Natural Sciences and Engineering Research Council of Canada)
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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.
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