Physiological role of the blood-brain barrier transportsome

2009 Fiscal Year Final Research Report

• Project/Area Number: 17081002
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: TERASAKI Tetsuya Tohoku University, 大学院・薬学研究科, 教授 (60155463)
• Co-Investigator(Kenkyū-buntansha): OHTSUKI Sumio 東北大学, 大学院・薬学研究科, 准教授 (60323036)
• Project Period (FY): 2005 – 2009
• Keywords: 血液脳関門 / 血液脳脊髄液関門 / トランスポートソーム / 膜輸送複合体 / P-糖蛋白質

Research Abstract

The quantification method of transporter proteins was established by means of mass spectrometer. The protein expression amounts and transport activities of transporters were determined in brain capillary endothelial cells, which form the blood-brain barrier. As a result, the function of glucose transporter 1 and multidrug resistant protein 1a (mdr1a) was able to be re-constructed in normal conditions, while the function of mdr1a in inflammation conditions was not. It was also suggested that the transportsome was involved in a part of physiological function of the blood-brain barrier.

Research Products

• [Journal Article] Involvement of multidrug resistance- associated protein 4 in efflux transport of prostaglandin E2 across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins. (2010)
  • Author(s): S. Akanuma, K. Hosoya, S. Ito, M. Tachikawa, T. Terasaki, S. Ohtsuki
  • Journal Title: J. Pharmacol. Exp. Ther 99 Pages: 912-919
  • Peer Reviewed
• [Journal Article] Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect. (2010)
  • Author(s): Nakazawa Y, Okura T, Shimomura K, Terasaki T, Deguchi Y
  • Journal Title: J. Pharm. Sci 99 Pages: 467-474
  • Peer Reviewed
• [Journal Article] The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters. (2009)
  • Author(s): achikawa M, Kasai Y, Yokoyama R, Fujinawa J, Ganapathy V, Terasaki T, Hosoya K
  • Journal Title: J. Neurochem 111 Pages: 499-509
  • Peer Reviewed
• [Journal Article] Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercapto- purine. (2009)
  • Author(s): Hosoya K, Makihara A, Tsujikawa Y, Yoneyama D, Mori S, Terasaki T, Akanuma S, Tomi M, Tachikawa M
  • Journal Title: J Pharmacol Exp Ther 329 Pages: 87-93
  • Peer Reviewed
• [Journal Article] Targeted Absolute Proteomicsを用いたトランスポーターの新しい研究展開 (2009)
  • Author(s): 大槻純男、上家潤一、寺崎哲也
  • Journal Title: 遺伝子医学MOOK12 Pages: 48-54
  • Peer Reviewed
• [Journal Article] 中枢への薬物分布におけるトランスポーターの機能と役割 (2009)
  • Author(s): 大槻純男
  • Journal Title: 日本薬理学雑誌 134 Pages: 83-86
  • Peer Reviewed
• [Journal Article] mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting. (2008)
  • Author(s): Ohtsuki S, Yamaguchi H, Katsukura Y, Asashima T, Terasaki T
  • Journal Title: J. Neurochem 104 Pages: 147-154
  • Peer Reviewed
• [Journal Article] Expression of nuclear receptor mRNA and liver X receptor-mediated regulation of ABC transporter A1 at rat blood-brain barrier. (2008)
  • Author(s): Akanuma S, Hori S, Ohtsuki S, Fujiyoshi M, Terasaki T
  • Journal Title: Neurochem. Int 52 Pages: 669-674
  • Peer Reviewed
• [Journal Article] Quantitative atlas of membrane transporter proteins: Development and application of a highly sensitive simultaneous LC/MS/MS method combined with novel in-silico peptide selection criteria. (2008)
  • Author(s): Kamiie J, Ohtsuki S, Iwase R, Ohmine K, Katsukura Y, Yanai K, Sekine Y, Uchida Y, Ito S, Terasaki T
  • Journal Title: Pharm. Res 25 Pages: 1469-1483
  • Peer Reviewed
• [Journal Article] 血液脳関門におけるモノアミン関連トランスポーターの役割 (2008)
  • Author(s): 大槻純男
  • Journal Title: Clinical Neuroscience 26 Pages: 1077-1080
  • Peer Reviewed
• [Journal Article] Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. (2007)
  • Author(s): M. Belanger, T. Asashima, S. Ohtsuki, H. Yamaguchi, S. Ito, T. Terasaki
  • Journal Title: Neurochem. Int 50 Pages: 95-101
  • Peer Reviewed
• [Journal Article] 24S-Hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical- and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression. (2007)
  • Author(s): Fujiyoshi M, Ohtsuki S, Hori S, Tachikawa M, Terasaki T
  • Journal Title: J. Neurochem 100 Pages: 968-978
  • Peer Reviewed
• [Journal Article] Establishing a method to isolate rat brain capillary endothelial cells by magnetic cell sorting and dominant mRNA expression of multidrug resistance-associated protein 1 and 4 in highly purified rat brain capillary endothelial cells. (2007)
  • Author(s): Ohtsuki S, Yamaguchi H, Asashima T, Terasaki T
  • Journal Title: Pharm. Res 24 Pages: 688-694
  • Peer Reviewed
• [Journal Article] Correlation of induction of ATP binding cassette transporter A5 (ABCA5) and ABCB1 mRNAs with differentiation state of human colon tumor. (2007)
  • Author(s): Ohtsuki S, Kamoi M, Watanabe Y, Suzuki H, Hori S, Terasaki T
  • Journal Title: Biol. Pharm. Bull 30 Pages: 1144-1146
  • Peer Reviewed
• [Journal Article] Brain-to-blood elimination of 24S-hydroxy- cholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier. (2007)
  • Author(s): Ohtsuki S, Ito S, Matsuda A, Hori S, Abe T, Terasaki T
  • Journal Title: J. Neurochem 103 Pages: 1430-1438
  • Peer Reviewed
• [Journal Article] Multichannel Liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. (2007)
  • Author(s): Uchida Y, Kamiie J, Ohtsuki S, Terasaki T
  • Journal Title: Pharm. Res 24 Pages: 2281-2296
  • Peer Reviewed
• [Journal Article] Involvement of organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. (2006)
  • Author(s): Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M
  • Journal Title: J Neurochem 96(4) Pages: 1051-1059
  • Peer Reviewed
• [Journal Article] In vivo delivery of small interfering RNA targeting brain capillary endothelial cells. (2006)
  • Author(s): Hino T, Yokota T, Ito S, Nishina K, Kang YS, Mori S., Hori S, Kanda T, Terasaki T, Mizusawa H
  • Journal Title: Biochem Biophys Res Commun 340(1) Pages: 263-267
  • Peer Reviewed
• [Journal Article] ATP-binding cassette transporter G2 mediates the efflux of phototoxins on the luminal membrane of retinal capillary endothelial cells. (2006)
  • Author(s): Asashima T, Hori S, Ohtsuki S, Tachikawa M, Watanabe M, Mukai C, Kitagaki S, Miyakoshi N, Terasaki T
  • Journal Title: Pharm Res 23 Pages: 1235-1242
  • Peer Reviewed
• [Journal Article] Major involvement of low-density lipoprotein receptor- related protein 1 in the clearance of plasma free amyloid beta-peptide by the liver. (2006)
  • Author(s): Tamaki C., Ohtsuki S, Iwatsubo T, Hashimoto T, Yamada K, Yabuki C, Terasaki T
  • Journal Title: Pharm Res 23 Pages: 1407-1416
  • Peer Reviewed
• [Journal Article] Modulation and compensation of the mRNA expression of energy related transporters in the brain of glucose transporter 1-deficient mice. (2006)
  • Author(s): Ohtsuki S, Kikkawa T, Hori S, Terasaki T
  • Journal Title: Biol. Pharm. Bull 29 Pages: 1587-1591
  • Peer Reviewed
• [Journal Article] 脳関門輸送の分子機構と脳へのDDS (2006)
  • Author(s): 大槻純男
  • Journal Title: DDS学会誌 21 Pages: 102-110
  • Peer Reviewed
• [Journal Article] Increased JNK Phosphorylation and oxidative stress in response to increased glucose flux through increased GLUT1 expression in rat retinal endothelial cells. (2005)
  • Author(s): Zhou J, Deo BK, Hosoya K, Terasaki T, Obrosova IG, Brosius III FC, Kumagai AK
  • Journal Title: Invest Ophthalmol Vis Sci 46 Pages: 3403-3410
  • Peer Reviewed
• [Journal Article] Distinct spatio-temporal expression of ABCA and ABCG transporters in the developing and adult mouse brain. (2005)
  • Author(s): Tachikawa M, Watanabe M, Hori S, Fukaya M, Ohtsuki S, Asashima T, Terasaki T
  • Journal Title: J Neurochem 95 Pages: 294-304
  • Peer Reviewed
• [Journal Article] Characterization of the organic cation transporter SLC22A16: a doxorubicin importer. (2005)
  • Author(s): Okabe M, Unno M, Harigae H, Kaku M, Okitsu Y, Sasaki T, Mizuno T, Shiiba K, Takanaga H, Terasaki T, Matsuno S, Sasaki I, Ito S, Abe T
  • Journal Title: Biochem Biophys Res Commun 333 Pages: 754-762
  • Peer Reviewed
• [Presentation] Prediction of In Vivo ADME Based on the Transporter Protein Quantification. (2009)
  • Author(s): T. Terasaki
  • Organizer: 2009 AAPS Annual Meeting and Exposition
  • Place of Presentation: Los Angels, CA, USA
  • Year and Date: 20091108-20091112
• [Presentation] 22th Biennal Meeting of the International Society for Neurochemistry (ISN) (2009)
  • Author(s): T. Terasaki
  • Organizer: American Society Neurochemistry Joint Meeting
  • Place of Presentation: Busan, Korea
  • Year and Date: 20090823-20080828
• [Presentation] Transporter protein quantification for the future of transporter science. Advanced Technologies for the Future of Transporter Sciences (2009)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: 36th Congress of the International Union of Physiological Sciences
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20090728-20090801
• [Presentation] Quantitative transporter protein analysis of human brain capillary endothelial (2009)
  • Author(s): T. Terasaki
  • Organizer: 8the Cerebral Vascular Biology International Conference (CVB2009)
  • Place of Presentation: Sendai, Japan
  • Year and Date: 20090628-20090702
• [Presentation] Pharmacoproteomics (PPx): Quantitative Targeted Absolute Proteomics (QTAP) based Pharmacokinetics as a New Path for the Drug Discovery and Development (2009)
  • Author(s): T. Terasaki
  • Organizer: Asian Federation for Pharmacutical Sciences 2009
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2009-10-16
• [Presentation] New approach to drug design by quantitative membrane proteomics (2009)
  • Author(s): S. Ohtsuki
  • Organizer: Special lecture in Seoul National University
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-05-20
• [Presentation] Pharmacoproteomics as a novel method for the prediction of drug delivery to the brain (2009)
  • Author(s): T. Terasaki, Y. Uchida, H. Kawakami, Y. Katsukura, J. Kamiie, S. Ohtsuki
  • Organizer: 7th Retrometabolism Based Drug Design and Targeting Conference
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-05-11
• [Presentation] Targeted proteomics analysis of tight junction proteins expressed at the blood-brain barrier (2008)
  • Author(s): S. Ohtsuki, S. Murata, Y. Katsukura, J. Kamiie, P.O. Couraud, T. Terasaki
  • Organizer: The 11th international symposium on "Signal transduction in the Blood-Brain Barriers"
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 20080918-20080920
• [Presentation] Targeted proteomics of the BBB tight junction (2008)
  • Author(s): S. Ohtsuki
  • Organizer: Gordon Research conference "Barriers of the CNS"
  • Place of Presentation: Tilton, NH. USA
  • Year and Date: 20080622-20080627
• [Presentation] Award Lecture for New Investigator Award (2008)
  • Author(s): S. Ohtsuki
  • Organizer: 2nd ISSX Asian Pacific Regional Meeting
  • Place of Presentation: Shanghai, China
  • Year and Date: 20080511-20080513
• [Presentation] Quantitative targeted proteomics as a new strategy for the blood-brain barrier research (2008)
  • Author(s): S. Ohtsuki
  • Organizer: 2008 the Pharmaceutical Society of Korea Metting
  • Place of Presentation: Jeju, Korea
  • Year and Date: 20080501-20080503
• [Presentation] Blood-Brain Barrier Pharmacoproteomics (PPx): Targeted absolute proteomics-based pharmacokinetics as a new path for the blood-brain barrier research (2008)
  • Author(s): T. Terasaki, Y. Uchida, J. Kamiie, S. Ohtsuki
  • Organizer: BLOOD-BRAIN BARRIER CONSORTIUM CLUB Symposium: 'The impact of efflux transports on CNS drug distribution'
  • Place of Presentation: Gordon Museum, Hodgkin Building, King's College Guy's Campus, London, United Kingdom
  • Year and Date: 2008-11-14
• [Presentation] Targeted Absolute Proteomics as A New Path to the Pharmaceutical and Biomedical Sciences both for Academia and Industry (2008)
  • Author(s): T. Terasaki
  • Organizer: Special Seminar at the University Paris 5, Faculty of Pharmaceutical Sciences
  • Place of Presentation: Paris, France 14.
  • Year and Date: 2008-04-21
• [Presentation] Targeted Absolute Proteomics as A New Path to the Biomedical Sciences (2008)
  • Author(s): T. Terasaki
  • Organizer: Leibniz-Institut of Molekulare Pharmakologie (FMP)
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2008-04-14
• [Presentation] Targeted absolute proteomics as a new path to the drug discovery and development (2008)
  • Author(s): T. Terasaki
  • Organizer: Winter Symposium of Research Triangle Park -Drug Metabolizing Discussion Group (RTP-DMDG)
  • Place of Presentation: Chapel Hill, North Carolina, USA
  • Year and Date: 2008-03-05
• [Presentation] Quantitative proteomics as a path to new blood-brain barrier research (2007)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: Tenth Symposium Signal Transduction in the Blood-Brain Barriers
  • Place of Presentation: Potsdam, Germany
  • Year and Date: 20070913-20070916
• [Presentation] Functional expression of transporters for organic anion at the blood-brain barrier (2007)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: 7th Cerebral Vascular Biology International Conference
  • Place of Presentation: Ottawa, Canada
  • Year and Date: 20070624-20060628
• [Presentation] ain barrier transport protein for the brain drug delivery (2007)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: 6th Retrometabolism Based Drug Design and Targeting Conference
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 20070603-20070606
• [Presentation] Special Lecture: Quantitative proteomics in transporter biology as a new strategy of the drug delivery research (2007)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: International Workshop and Symposium on Transport, Metabolism and Disposition
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20070530-20070531
• [Presentation] Quantitative and Simultaneous LC-MS/MS Analysis for Membrane Proteins: Its Application for the Blood-Brain Barrier Biology (2006)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: Invited lecture at Seminar of Institut Cochin
  • Place of Presentation: Paris, France
  • Year and Date: 2006-12-22
• [Presentation] Quantitative proteomics for membrane proteins as a new strategy for the blood-brain barrier biology (2006)
  • Author(s): T. Terasaki, J. Kamiie, S. Ohtsuki
  • Organizer: Invited lecture at Seminar of Universite d'Atrois
  • Place of Presentation: Lens, France
  • Year and Date: 2006-12-20
• [Presentation] Brain-to-blood efflux transporters at the blood brain barrier as a CNS detoxifying system (2005)
  • Author(s): T. Terasaki, S. Ohtsuki
  • Organizer: 1th Indo-Japanese Conference on Advances in Pharmaceutical Research and Technology - with special emphasis on Drug Discovery and Drug Delivery
  • Place of Presentation: Mumbai, India
  • Year and Date: 20051125-20051129
• [Book] A novel relationship between creatine transport at the blood-brain and blood-retinal barriers, Creatine biosynthesis, and its use for brain and retinal energy homeostasis (2007)
  • Author(s): M. Tachikawa, K. Hosoya, S. Ohtsuki, T. Terasaki
  • Total Pages: 83-98
  • Publisher: Springer