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This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.015800v1 35/11/1996    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maeng, H.-J. Articles by Chung, S.-J. Search for Related Content PubMed PubMed Citation Articles by Maeng, H.-J. Articles by Chung, S.-J.

Functional Induction of P-glycoprotein in the Blood-Brain Barrier of Streptozotocin-Induced Diabetic Rats: Evidence for the Involvement of Nuclear Factor-B, a Nitrosative Stress-Sensitive Transcription Factor, in the Regulation

Department of Pharmaceutics, College of Pharmacy (H.-J.M., M.-H.K., H.-E.J., D.-D.K., C.-K.S., S.-J.C.), and National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences (S.M.S., S.G.K.), Seoul National University, Seoul, Korea; and Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan (T.T.)

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-B (NF-B) and DNA binding activity of nuclear extracts to the NF-B 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-B-dependent mechanism.