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Drug Metabolism and Disposition Fast Forward
First published on July 30, 2007; DOI: 10.1124/dmd.107.015800

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Received for publication March 22, 2007.
Revised July 24, 2007.
Accepted for publication July 25, 2007.

Functional Induction of P-glycoprotein in the Blood Brain Barrier of Streptozotocin-induced Diabetic Rats: Evidence for the Involvement of NF-{kappa}B, a Nitrosative Stress-sensitive Transcription Factor, in the Regulation

Han-Joo Maeng 1, Mi-Hwa Kim 1, Hyo-Eon Jin 1, Sang Mi Shin 2, Takasi Tsuruo 3, Sang Geon Kim 2, Dae-Duk Kim 1, Chang-Koo Shim 1, Suk-Jae Chung 1*

1 Department of Pharmaceutics, College of Pharmacy,Seoul National University 2 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University 3 Graduate School of Pharmaceutical Science, The University of Tokyo

* Address correspondence to: E-mail: sukjae{at}plaza.snu.ac.kr

Abstract

The objective of this study was to investigate the transport kinetics of cyclosporin A, a well-known substrate for P-glycoprotein, across the blood-brain barrier (BBB), and the expression for the transporter in the brain of streptozotocin (STZ)-induced diabetic rats. The in vivo transport clearance of cyclosporine 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 MBEC4 cells, an in vitro model of the BBB, was also stimulated when slow NO-releasing donors were present, whereas the stimulation was absent for the case of rapid NO-releasing donors (e.g., SNAP and DETA). The stimulatory effect was highest for SNP and the functional induction associated with the increased mRNA and protein level for 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 NF-{kappa}B and DNA binding activity of nuclear extracts to the NF-{kappa}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-{kappa}B-dependent mechanism.


Key words: ABC transporters, blood-brain barrier, drug distribution, drug efflux, MRP, oxidative stress, p-glycoprotein, pharmacokinetics, transcriptional regulation, transporters




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