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Functional induction of P-glycoprotein in the blood-brain barrier of streptozotocin-induced diabetic rats: evidence for the involvement of nuclear factor-kappaB, a nitrosative stress-sensitive transcription factor, in the regulation

Cited 39 time in Web of Science Cited 39 time in Scopus
Authors
Maeng, Han-Joo; Kim, Mi-Hwa; Jin, Hyo-Eon; Shin, Sang Mi; Tsuruo, Takasi; Kim, Sang Geon; Kim, Dae-Duk; Shim, Chang-Koo; Chung, Suk-Jae
Issue Date
2007
Publisher
American Society for Pharmacology and Experimental Therapeutics
Citation
Drug Metab Dispos 35:1996-2005
Keywords
ATP-Binding Cassette Transporters/genetics/metabolismActive Transport, Cell Nucleus/drug effectsAnimalsAntioxidants/pharmacologyBlood Glucose/metabolismBlood-Brain Barrier/*metabolismBlotting, WesternCell LineCell Nucleus/metabolismDiabetes Mellitus, Experimental/blood/*metabolismEndothelial Cells/cytology/drug effects/metabolismFree Radical Scavengers/pharmacologyGene Expression/drug effectsMaleMiceNF-kappa B/*metabolismNitric Oxide Donors/pharmacologyNitrites/blood/metabolismP-Glycoprotein/genetics/*metabolismP-Glycoproteins/genetics/metabolismRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionSuperoxides/metabolism
Abstract
The objective of this study was to investigate the transport kinetics of cyclosporin A, a well known substrate for P-glycoprotein (P-gp), across the blood-brain barrier (BBB), and the expression of the transporter in the brain of streptozotocin-induced diabetic rats. The in vivo transport clearance of cyclosporin A was significantly reduced in diabetic rats compared with that in the control. The decreased transport was associated with the increased level of mRNA and the protein for P-glycoprotein in the rat brain. The functional activity of the efflux transporter in mouse brain capillary endothelial (MBEC4) cells, an in vitro model of the BBB, was also stimulated when slow nitric oxide (NO)-releasing donors were present, whereas the stimulation was absent in the case of rapid NO-releasing donors (e.g., S-nitroso-N-acetyl-dl-penicillamine and diethylenetriamine). The stimulatory effect was highest for sodium nitroprusside (SNP) and the functional induction associated with the increased mRNA and protein level of the transporter. The pretreatment of the cell with SNP along with ascorbate, methylene blue, or superoxide dismutase attenuated the induction of function and expression for P-glycoprotein, suggesting that the reaction product between superoxide and NO is involved in the induction of function and expression. The level of nuclear translocation of nuclear factor-kappaB (NF-kappaB) and DNA binding activity of nuclear extracts to the NF-kappaB consensus oligonucleotide was increased in MBEC4 cells pretreated with SNP. Taken together, these observations suggest that nitrosative stress leads to the up-regulation of the message for the efflux transporter and, ultimately, to the enhanced function, probably via a NF-kappaB-dependent mechanism.
ISSN
0090-9556 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17664251

http://hdl.handle.net/10371/29603
DOI
https://doi.org/10.1124/dmd.107.015800
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College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Journal Papers (저널논문_협동과정-임상약리학전공)
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