Identification of essential determinants for membrane localization of drug transporters and elucidation of their polarized transport mechanisms

• Project/Area Number: 19590142
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyoto University
• Principal Investigator: KATSURA Toshiya Kyoto University, 医学研究科, 准教授 (10283615)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 極性上皮細胞 / 薬物トランスポータ / 膜輸送 / 薬物動態 / 有機カチオントランスポータ / 細胞膜ターゲティング

Research Abstract

腎臓の近位尿細管に局在する薬物の運び屋タンパク質(トランスポータ)がどのように細胞膜に運ばれ機能するか、またその発現量がどのように規定されているか等を明らかにすることを目的として検討を行い、腎臓における薬物輸送を再現するモデル細胞の構築に成功し、また薬物トランスポータの発現量を規定する因子を同定することができた。さらに、トランスポータを全く発現しないマウスを作製し、その役割を明確にした。

Research Products

• [Journal Article] Targeted disruption of the multidrug and toxin extrusion 1 (matel) gene in mice reduces renal secretion of metformin (2009)
  • Author(s): Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui K.
  • Journal Title: Mol.Pharmacol. 75 Pages: 1280-1286
  • Peer Reviewed
• [Journal Article] Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells (2009)
  • Author(s): Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, Inui K.
  • Journal Title: J.Pharmacol.Exp.Ther. 329 Pages: 185-191
  • Peer Reviewed
• [Journal Article] Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity (2009)
  • Author(s): Kajiwara M, Terada T, Ogasawara K, Iwano J, Katsura T, Fukatsu A, Doi T, Inui K.
  • Journal Title: J.Hum.Genet. 54 Pages: 40-46
  • NAID: 10030728868
  • Peer Reviewed
• [Journal Article] Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity (2009)
  • Author(s): Moto Kajiwara, et al.
  • Journal Title: Journal of Human Genetics 54 Pages: 40-46
  • Peer Reviewed
• [Journal Article] Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformln in renal epithelial ceels (2009)
  • Author(s): Masahiro Tsuda, et al.
  • Journal Title: Journal of Pharmacology and Exerimental Therapeutics 329 Pages: 185-191
  • Peer Reviewed
• [Journal Article] Targeted disruption of the multidrug and toxin extrusion 1 (Matel) gene in mice reduces renal secretion of metformin (2009)
  • Author(s): Masahiro Tsuda, et al.
  • Journal Title: Molecular Pharmacology
  • Peer Reviewed
• [Journal Article] Regulation of basal core promoter activity of human organic cation transporter 1 (OCT1/SLC22A1). (2008)
  • Author(s): Kajiwara M, Terada T, Asaka J, Aoki M, Katsura T, Ikai I, Inui K.
  • Journal Title: Am.J.Physiol.Gastrointest. Liver Physiol. 295
  • Peer Reviewed
• [Journal Article] Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1 (2008)
  • Author(s): Sato T, Masuda S, Yonezawa A, Tanihara Y, Katsura T, Inui K.
  • Journal Title: Biochem.Pharmacol. 76 Pages: 894-903
  • Peer Reviewed
• [Journal Article] Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation (2008)
  • Author(s): Aoki M, Terada T, Kajiwara M, Ogasawara K, Ikai I, Ogawa O, Katsura T, Inui K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 295
  • Peer Reviewed
• [Journal Article] Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney (2008)
  • Author(s): Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T, Kamba T, Ogawa O, Inui K.
  • Journal Title: J.Hum.Genet. 53 Pages: 607-614
  • NAID: 10021249665
  • Peer Reviewed
• [Journal Article] Thyroid hormone regulates the expression and function of P-glycoprotein in Caco-2 cells (2008)
  • Author(s): Naoki Nishio, et al.
  • Journal Title: Pharmaceutical Research 25 Pages: 1037-1042
  • Peer Reviewed
• [Journal Article] Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney (2008)
  • Author(s): Ken Ogasawara, et al.
  • Journal Title: Journal of Human Genetics 53 Pages: 607-614
  • Peer Reviewed
• [Journal Article] Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation (2008)
  • Author(s): Masayo Aoki, et al.
  • Journal Title: American Journal of Physiology Renal Physiology 295
  • Peer Reviewed
• [Journal Article] Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis (2008)
  • Author(s): Jiarong Chen, et al.
  • Journal Title: American Journal of Physiology Renal Physiology 295
  • Peer Reviewed
• [Journal Article] Identification and functional characterization of a. novel human and rat riboflavin transporter, RFTl (2008)
  • Author(s): Atsushi Yonezawa, et al
  • Journal Title: American Journal of Physiology Cell Physiology 295
  • Peer Reviewed
• [Journal Article] Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1 (2008)
  • Author(s): Tomoko Sato, et al.
  • Journal Title: Biochemical Pharmacology 76 Pages: 894-903
  • Peer Reviewed
• [Journal Article] Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer (2008)
  • Author(s): Sachiko Yokoo, et al.
  • Journal Title: Drug Metabolism and Disposition 36 Pages: 2299-2306
  • Peer Reviewed
• [Journal Article] Regulation of basal core promoter activity of human organic cation transporter 1 (OCTl/SLC22Al) (2008)
  • Author(s): Moto Kajiwara, et al.
  • Journal Title: American Journal of Physiology Gastrointestinal and Liver Physiology 295
  • Peer Reviewed
• [Journal Article] Critical roles of Spl in gene expression of human and rat H+/organic cation antiporter MATE1 (2007)
  • Author(s): Kajiwara M, Terada T, Asaka J, Ogasawara K, Katsura T, Ogawa O, Fukatsu A, Doi T, Inui K.
  • Journal Title: Am.J.Physiol.Renal Physiol. 293
  • Peer Reviewed
• [Journal Article] Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity (2007)
  • Author(s): Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K.
  • Journal Title: Biochem.Pharmacol. 74 Pages: 477-487
  • Peer Reviewed
• [Journal Article] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusion/H+-organic cation antiporters (2007)
  • Author(s): Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K.
  • Journal Title: Biochem.Pharmacol. 74 Pages: 359-371
  • Peer Reviewed
• [Journal Article] Identification of essential histidine and cysteine residues of the H+/organic cation antiporter multidrug and toxin extrusion (MATE) (2007)
  • Author(s): Asaka J, Terada T, Tsuda M, Katsura T, Inui K.
  • Journal Title: Mol.Pharmacol. 71 Pages: 1487-1493
  • Peer Reviewed
• [Journal Article] Characterization of the basal promoter element of human organic cation transporter 2 gene (2007)
  • Author(s): Asaka J, Terada T, Ogasawara K, Katsura T, Inui K.
  • Journal Title: J.Pharmacol.Exp.Ther. 321 Pages: 684-689
  • Peer Reviewed
• [Journal Article] Pharmacokinetic significance of luminal multidrug and toxin extrusion 1 in chronic renal failure rats (2007)
  • Author(s): Nishihara K, Masuda S, JiL, Katsura T, Inui K.
  • Journal Title: Biochem.Pharmacol. 73 Pages: 1482-1490
  • Peer Reviewed
• [Journal Article] Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members(hOAT1, hOAT3, and hOCT2) (2007)
  • Author(s): Yuichi Uwai, et. al.
  • Journal Title: Pharmaceutical Research 24巻 Pages: 811-815
  • Peer Reviewed
• [Journal Article] Characterization of the basal promoter element of human organic cation transporter 2 gene (2007)
  • Author(s): Jun-ichi Asaka, et. al.
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics 321巻 Pages: 684-689
  • Peer Reviewed
• [Journal Article] Pharmacokinetic significance of luminal multidrug and toxin extrusion 1 in chronic renal failure (2007)
  • Author(s): Kumiko Nishihara, et. al.
  • Journal Title: Biochemical Pharmacology 73巻 Pages: 1482-1490
  • Peer Reviewed
• [Journal Article] Identification of essential histidine and cysteine residues of the H^+/organic cation antiporter multidrug and toxin extrusion(MATE) (2007)
  • Author(s): Jun-ichi Asaka, et. al.
  • Journal Title: Molecular Pharmacology 71巻 Pages: 1487-1493
  • Peer Reviewed
• [Journal Article] Hepatocyte nuclear factor-4α regulates the human organic anion transporter 1 gene in the kidney (2007)
  • Author(s): Ken Ogasawara, et. al.
  • Journal Title: American Journal of Physiology Renal Physiology 292巻
  • Peer Reviewed
• [Journal Article] Interaction and transport of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3 (2007)
  • Author(s): Yuichi Uwai, et. al.
  • Journal Title: Biochemical Pharmacology 74巻 Pages: 161-168
  • Peer Reviewed
• [Journal Article] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusion/H^+-organic cation antiporters (2007)
  • Author(s): Yuko Tanihara, et. al.
  • Journal Title: Biochemical Pharmacology 74巻 Pages: 359-371
  • Peer Reviewed
• [Journal Article] Cl-dependent upregulation of human organic anion transporters: different effects on transport kinetics between hOAT1 and hOAT3 (2007)
  • Author(s): Harumasa Ueo, et. al.
  • Journal Title: American Journal of Physiology Renal Physiology 293巻
  • Peer Reviewed
• [Journal Article] Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity (2007)
  • Author(s): Sachiko Yokoo, et. al.
  • Journal Title: Biochemical Pharmacology 74巻 Pages: 477-487
  • Peer Reviewed
• [Journal Article] Critical roles of Sp1 in gene expression of human and rat H^+/organic cation antiporter MATE1 (2007)
  • Author(s): Moto Kajiwara, et. al.
  • Journal Title: American Journal of Physiology Renal Physiology 293巻
  • Peer Reviewed
• [Presentation] Comparison of functional characteristics of H+/organic cation antiporters MATE1 and MATE2-K (2008)
  • Author(s): Tsuda M, et al.
  • Organizer: 2008 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA.
  • Year and Date: 2008-11-18
• [Presentation] Regulation of kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) by DNA methylation (2008)
  • Author(s): Ogasawara K, et al.
  • Organizer: 2008 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2008-11-18
• [Presentation] Regulation of kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) by DNA methylation (2008)
  • Author(s): Ken Ogasawara, et al.
  • Organizer: 2008 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
  • Place of Presentation: Atlanta, U.S.A.
  • Year and Date: 2008-11-18
• [Presentation] Comparison of functional characteristics of H+/organic cation antiporters MATE1 and MATE2-K (2008)
  • Author(s): Masahiro Tsuda, et al.
  • Organizer: 2008 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
  • Place of Presentation: Atlanta, U.S.A.
  • Year and Date: 2008-11-18
• [Presentation] Transcriptome analysis using purified proximal tubules in progressive renal failure rats (2008)
  • Author(s): Kumiko Nishihara, et al.
  • Organizer: 2008 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
  • Place of Presentation: Atlanta, U.S.A.
  • Year and Date: 2008-11-17
• [Presentation] ヒトMATE1の機能的発現における翻訳後プロセシングの重要性 (2008)
  • Author(s): 岩野淳子, ら
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本市
  • Year and Date: 2008-10-31
• [Presentation] ヒトMTE1の機能的発現における翻訳後プロセシングの重要性 (2008)
  • Author(s): 岩野淳子, ら
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本市
  • Year and Date: 2008-10-31
• [Presentation] Pathophysiological roles of renal organic anion transporter 3 (OAT3) in the cholestasis (2008)
  • Author(s): Tomohiro Terada, et al.
  • Organizer: International Society for the Study of Xenobiotics 2nd Pacific Asian Regional Meeting
  • Place of Presentation: Shanghai, People's Republic of China
  • Year and Date: 2008-05-11
• [Presentation] Promoter analyses of human and rat H+/organic cation antiporter (MATE1) (2007)
  • Author(s): Kajiwara M, et al.
  • Organizer: 8th International Society for the Study Xenobiotics International Meeting
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2007-10-10
• [Presentation] Promoter analyses of human and rat H^+/organic cation antiporter (MATE1) (2007)
  • Author(s): Moto Kajiwara, et. al.
  • Organizer: 8th International Society for the Study Xenobiotics International Meeting
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2007-10-10
• [Presentation] Expressional and functional changes in rat H+/organic cation antiporter MATE1 in chronic renal failure (2007)
  • Author(s): Nishihara K, et al.
  • Organizer: Biomedical Transporters 2007
  • Place of Presentation: Bem, Switzerland
  • Year and Date: 2007-08-13
• [Presentation] Structural characteristics and substrate specificity of hMATE2-K (2007)
  • Author(s): Tanihara Y, et al.
  • Organizer: Biomedical Transporters 2007
  • Place of Presentation: Bern, Switzerland
  • Year and Date: 2007-08-13
• [Presentation] Expressional and functional changes in rat H^+/organic cation antiporter MATE1 in chronic renal failure (2007)
  • Author(s): Kumiko Nishihara, et. al.
  • Organizer: Biomedical Transporters 2007
  • Place of Presentation: Bern, Switzerland
  • Year and Date: 2007-08-13
• [Presentation] OCT and Mate families are key transporters in platinum agents-induced nephrotoxicity (2007)
  • Author(s): Yokoo S, et al.
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2007-06-21
• [Presentation] Drug-drug interaction and its importance for the safe and effective pharmacotherapy (2007)
  • Author(s): Katsura T, et al.
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2007-06-20
• [Presentation] hOCT/hMATEダブルトランスフエクタントの構築と経細胞輸送解析 (2007)
  • Author(s): 佐藤朋子, ら
  • Organizer: 日本薬剤学会第22年会
  • Place of Presentation: さいたま市
  • Year and Date: 2007-05-22
• [Presentation] hOCT/hMATEダブルトランスフェクタントの構築と経細胞輸送解析 (2007)
  • Author(s): 佐藤朋子, ら
  • Organizer: 日本薬剤学会第22年会
  • Place of Presentation: さいたま市
  • Year and Date: 2007-05-22
• [Presentation] Functional roles of cystein and histidine residues in rat H+/organic cation antiporter MATE1 (2007)
  • Author(s): Terada T, et al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-25
• [Presentation] Identification of a driving force of H+/organic cation antiporter rat and human MATE1 using plasma membrane vesicles (2007)
  • Author(s): Tsuda M, et al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-25
• [Presentation] Functional roles of cystein and histidine residues in rat H^+/organic cation antiporter MATE1 (2007)
  • Author(s): Tomohiro Terada, et. al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-25
• [Presentation] Identification of a driving force of H^+/organic cation antiporter rat and human MATE1 using plasma membrane vesicles (2007)
  • Author(s): Masahiro Tsuda, et. al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-25
• [Presentation] Regulatory mechanisms for gene expression of human organic anion transporters (2007)
  • Author(s): Ken Ogasawara, et. al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-25
• [Presentation] Transcriptional activation of MDR1 gene by thyroid hormone receptor (2007)
  • Author(s): Toshiya Katsura, et. al.
  • Organizer: Pharmaceutical Sciences World Congress 2007
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 2007-04-24
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~yakuzai/kenky.html
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~yakuzai/kenky.html