5 research outputs found
Fluorescein-methotrexate transport in rat choroid plexus analyzed using confocal microscopy
Constitutive Androstane Receptor-Mediated Up-Regulation of ATP-Driven Xenobiotic Efflux Transporters at the Blood-Brain BarrierS⃞
ATP-driven efflux transporters at the blood-brain barrier both protect against
neurotoxicants and limit drug delivery to the brain. In other barrier and excretory
tissues, efflux transporter expression is regulated by certain ligand-activated
nuclear receptors. Here we identified constitutive androstane receptor (CAR) as a
positive regulator of P-glycoprotein, multidrug resistance-associated protein 2
(Mrp2), and breast cancer resistance protein (BCRP) expression in rat and mouse brain
capillaries. Exposing rat brain capillaries to the CAR activator, phenobarbital (PB),
increased the transport activity and protein expression (Western blots) of
P-glycoprotein, Mrp2, and BCRP. Induction of transport was abolished by the protein
phosphatase 2A inhibitor, OA. Similar effects on transporter activity and expression
were found when mouse brain capillaries were exposed to the mouse-specific CAR
ligand, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). In brain capillaries
from CAR-null mice, TCPOBOP did not increase transporter activity. Finally, treating
mice with 0.33 mg/kg TCPOBOP or rats with 80 mg/kg PB increased P-glycoprotein-,
Mrp2-, and BCRP-mediated transport and protein expression in brain capillaries
assayed ex vivo. Thus, CAR activation selectively tightens the blood-brain barrier by
increasing transport activity and protein expression of three xenobiotic efflux
pumps