Irradiation of rat brain reduces P-glycoprotein expression and function.
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 [(11)C]carvedilol uptake using quantitative autoradiography. Irradiation increased [(11)C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [(11)C]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 [(11)C]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.
Bart
J
J
Department of Pathology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
Nagengast
W B
WB
Coppes
R P
RP
Wegman
T D
TD
van der Graaf
W T A
WT
Groen
H J M
HJ
Vaalburg
W
W
de Vries
E G E
EG
Hendrikse
N H
NH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism / Q000528:radiation effects*; D002227:Carbazoles / Q000378:metabolism; D000077261:Carvedilol; D007150:Immunohistochemistry; D008297:Male; D011412:Propanolamines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol