bcrp - publications

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1. Mol Pharmacol. 2012 Jan 19. [Epub ahead of print]

Regulation of Breast Cancer Resistant Protein (BCRP) by Peroxisome
Proliferator-Activated Receptor Alpha (PPARα) in Human Brain Microvessel
Endothelial Cells.

Hoque MT, Robillard KR, Bendayan R.

University of Toronto.

Breast cancer resistance protein (BCRP/ABCG2, an ATP-Binding Cassette (ABC)
membrane-associated drug efflux transporter, is known to localize at the
blood-brain barrier (BBB) and can significantly restrict xenobiotic permeability
in the brain. The objective of this study is to investigate the regulation of
BCRP functional expression by peroxisome proliferator-activated receptor alpha
(PPARα), a ligand-activated transcription factor primarily involved in lipid
metabolism, in a cerebral microvascular endothelial cell culture system
(hCMEC/D3), representative of human BBB. We demonstrate that PPARα selective
ligands (i.e., clofibrate, GW7647) significantly induce BCRP mRNA and protein
expression in a time and concentration-dependent manner, while pharmacological
inhibitors (i.e., MK886; GW6471) prevent this induction. Using [3H]-mitoxantrone,
an established BCRP substrate, we observe a significant reduction in its cellular
accumulation by monolayer cells treated with clofibrate suggesting increased BCRP
efflux activity. Furthermore, we show a significant decrease in BCRP protein
expression and function when PPARα is downregulated by small interfering RNA.
Applying chromatin-immunoprecipitation and quantitative real-time PCR, we observe
that clofibrate treatment increases PPARα binding to the peroxisome proliferator
response element within ABCG2 gene promoter. This study provides the first
evidence of direct BCRP regulation by PPARα in a human in vitro BBB model and
suggests new targeting strategies for either improving drug brain bioavailability
or increasing neuroprotection.

PMID: 22266374 [PubMed - as supplied by publisher]