P‐glycoprotein expression in rat brain endothelial cells: 
evidence for regulation by transient oxidative stress

Abstract

During ischaemia/reperfusion, cells of the blood±brain barrier are subjected to oxidative stress. This study uses primary cultured rat brain endothelial cells to examine the effect of such stresses on expression of multidrug transporters. H 2 O 2 up to 500 lM applied to cell monolayers caused a concentration-dependent increase in expression of P-glycoprotein (Pgp) but not of multidrug resistance-associated protein (Mrp1). Concentrations > 250 lM H 2 O 2 decreased cell viability. Application of 100 lM H 2 O 2 caused a signi®cant increase after 48 h in Pgp functional activity, as assessed from [ 3 H]vincristine accumulation experiments. At this concentration, H 2 O 2 produced a transient increase within 10 min followed by a sustained decrease in levels of intracellular reactive oxygen species (iROS), detectable by¯ow cytometry. Reoxygenation of cell monolayers after 6 h hypoxia gave rise to a similar transient increase in iROS and this also led to increased Pgp expression by 24 h. Increases were also observed within 4 h after both H 2 O 2 and hypoxia/reoxygenation treatments in mdr1a and mdr1b mRNA. Evidence suggests this was due to enhanced transcription rather than mRNA stabilization. Therefore, oxidative stress, by changing Pgp expression, may affect movement of Pgp substrates in and out of the brain.

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

“…This suggests that a tight dose response relationship exists in the regulation of the mdr-1 gene by ROS. 16,19,20 The observed upregulation of P-glycopotein may be related to its anti-apoptotic properties, which have been previously reported and are presumably linked to P-glycoproteinmediated overexpression of the anti-apoptotic Bcl-xL protein. [21][22][23] Hyperthermia-induced upregulation of P-glycoprotein may be associated to an elevation of intracellular ROS levels.…”

c-Jun NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1α–Dependent P-Glycoprotein Expression in Hypoxia

“…ROS have been implicated in the activation of JNK and MDR1 (29,30). Furthermore, it has been reported that mitochondrial ROS production is increased in hypoxia (31).…”

The Antidepressant Clomipramine Regulates Cortisol Intracellular Concentrations and Glucocorticoid Receptor Expression in Fibroblasts and Rat Primary Neurones

“…This isoform is predominantly expressed in the adrenal and the ovaries (Lee et al, 2001), but is also expressed in the brain (Regina et al, 1998), particularly in the hippocampus (Kwan et al, 2002). Although mdr1b PGP has not been detected in brain capillaries (Regina et al, 1998), it is expressed in rat brain endothelial cells in vitro (Felix and Barrand, 2002). Consistent with this, mice that are knockout for mdr1a and mdr1b PGP show increased access of corticosterone to the brain (although this effect is smaller than that on cortisol) and increased negative feedback on the HPA axis by corticosterone (Uhr et al, 2002).…”