Irradiation of rat brain reduces P-glycoprotein expression and function

J. Bart, W. B. Nagengast, R. P. Coppes, T. D. Wegman, W. T.A. Van Der Graaf, H. J.M. Groen, W. Vaalburg, E. G.E. De Vries*, N. H. Hendrikse

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The blood-brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2-25 Gy followed by 10 mg kg-1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg -1), or with fractionated irradiation (4 x 5 Gy) followed by CsA (10 mg kg-1) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [11C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11C]carvedilol uptake dose-dependently in both hemispheres, but more (P<0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [11C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.

Original languageEnglish
Pages (from-to)322-326
Number of pages5
JournalBritish Journal of Cancer
Issue number3
Publication statusPublished - 31 Jul 2007

Cite this