2003 Fiscal Year Annual Research Report

ゲノム戦略に基づく高尿酸血症治療薬の創製

Research Project

Project/Area Number	14207004
Research Institution	Kyorin University
Principal Investigator	遠藤仁杏林大学, 医学部, 教授 (20101115)
Co-Investigator(Kenkyū-buntansha)	安西尚彦杏林大学, 医学部, 助手 (70276054) 細山田真杏林大学, 医学部, 講師 (00291659) 金井好克杏林大学, 医学部, 教授 (60204533) 入部雄司杏林大学, 医学部, 助手 (20348618)
Keywords	ゲノム / 尿酸トランスポーター / 尿酸 / 特発性低尿酸血症 / 痛風 / イーストツーハイブリド法 / PDZK 1 / ベンズプロマロン
Research Abstract	尿酸は、ヒトにおけるプリン代謝最終産物であるが、その生理的機能や腎内輸送機構、さらに痛風などの生活習慣病の病態との詳細な関連、並びに治療薬の開発における分子標的など多くが不明であった。そこで本研究は、本研究代表者らが同定した血液中の尿酸値を制御する腎に存在する新しい尿酸トランスポーター(URAT1)を用いて、ゲノム戦略に基づく高尿酸血症治療薬の創製の基盤形成を目的として行った。14年度に樹立したURAT1安定発現細胞を用いて、ベンズブロマロン、ピラジンカルボン酸、ロサルタン、インドメサシン、フロセミドなどの抑制効果が示され、すでにアフリカツメガエル卵母細胞発現系で明らかにされたURAT1の薬物感受性が安定発現細胞においても確認された。尿酸の腎内輸送は複雑で2回の再吸収と1回の分泌が想定されている。従って第二の尿酸トランスポーターの存在を想定し、ヒト及びマウスのゲノム及びEST(expressed sequence tag)データベースの検索を行い、十数種の新規配列を明らかにした。これらに関してノーザンブロットによるスクリーニングを行い、腎に発現するものについて、アフリカツメガエル卵母細胞発現系を用いて、機能解析を行った。その結果、新規トランスポーターのひとつに尿酸輸送活性を見い出し、その機能解析及び組織細胞局在の検討が進行中である。さらにURAT1の生体における機能的役割を明らかにする目的で、遺伝子欠失動物作製が進行中である。これに先立ち、マウスURAT1をマウス腎cDNAライブラリーより単離し、その尿酸輸送活性を明らかにした。このcDNAをもとにクローニングしたゲノムDNAを、ターゲティングベクター作製のために使用した。加えて、URAT1機能制御蛋白の同定を含めた制御機構の解析を進行させており、URAT1を標的としたゲノム創薬へ向けた基盤整備が整いつつある。

Research Products
(21 results)

All Other

All Publications (21 results)

[Publications] Enomoto, A., Kimura, H., Chairoungdua, Okubo, M., Yamada, K., Hosoyamada, M., Shibasaki, T., Endou, H.: "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes."Toxicol.Applied Pharmacol.. 187. 162-167 (2003)
[Publications] Enomoto, A., Takeda, M., Taki, K., Takayama, F., Noshiro, R., Niwa, T., Endou, H.: "Interactions of human organic anion as well as carion transporters with indoxyl sulfate."Euro.J.Pharmacol.. 466. 13-20 (2003)
[Publications] Satoh, H., Moriyama, N., Hara, C., Yamada, H., Horita, S., Kunimi, M., Tsukamoto, K., Iso-o, N., Inatomi, J., Kawakami, H., Kudo, A., Endou, H., Igarashi, T., Goto, A., Fujita T, Seki G: "Localization of Na^+-HCO_3^- cotransporter (NBC-1) variants in rat and human pancreas."Am.J.Physiol.Cell Physiol.. 284. C729-C737 (2003)
[Publications] Kanai, Y., Endou, H.: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)
[Publications] Hasegawa, M., Kusuhara, H., Endou, H., Sugiyama, Y.: "Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat."J.Pharmacol.Exp.Ther.. 305(3). 1087-1097 (2003)
[Publications] Jutabha, P., Kanai, Y., Hosoyamada, M., Chairoungdua, A., Kim, D.K., Iribe, Y., Babu, E., Kim, J.Y., Anzai, N., Chatsudthipong, V., Endou, H.: "Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule."J.Biol.Chem.. 278(30). 28930-27938 (2003)
[Publications] Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, Endou H, Naito M, Tsuruo T, Terasaki T: "Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment."J Pharmacol Exp Ther.. 302(1). 225-231 (2003)
[Publications] Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am J Kidney Dis.. 42(6). 1287-1292 (2003)
[Publications] Babu E, kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H.: "Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters."J Biol Chem.. 278(44). 43838-43845 (2003)
[Publications] Kim GH, Na KY, Kim SY, Joo KW, Oh YK, Chae SW, Endou H, Han JS.: "Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney."Nephrol Dial Transplant.. 18(8). 1505-1511 (2003)
[Publications] Alebouyeh M, Takeda M, Onozato ML, Tojo A, Noshiro R, Hasannejad H, Inotaomi J, Narikaw S, Huang XL, Khamdang, Anzai N, Endou H: "Expression of human organic anion transorters in the choroid plexus and their interactions with neurotransmitter metabolites."J Pharmachol sci.. 93. 430-436 (2003)
[Publications] Yoon JH, Kim YB, Kanai Y, Endou H, Kim DK: "Sequential Increases in 4F2hc expression during DMBA-induced hamster buccal pouch cacinogenesis."Anticancer Res.. 23. 3877-3882 (2003)
[Publications] Tanaka M., Itoh K., Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am.J.Kidney Des.. 42(6). 1287-1292 (2003)
[Publications] Takeda M, Norshio R, Onozato ML, Tojo A, Hasannejad H, Hang XL, Narikawa S, Endou H.: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-GoA reductase inhibitors."Eur.J.Pharmacol.. 483. 133-138 (2004)
[Publications] Sakata T, Anzai N, Shin HJ, Norhiro R, Hirata T, Yokoyama H, Kanai Y, Endou H.: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem Biophys Res Comm.. 313. 789-793 (2004)
[Publications] Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onodera ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H.: "Interactions of human organic anion transporters with diuretics."J Pharmacol Exp Ther.. 308(3). 1021-1029 (2004)
[Publications] Khamdan S, Takeda M, Shimoda M, Noshiro Ri, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Hitoshi E: "Interactions of human- and rat-organic anion transporters with pravastatih and cimetidine."J Pharmachol sci.. 94. 197-202 (2004)
[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."Biochem Biophys Res Comm.. 94. 297-304 (2004)
[Publications] Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y.: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)
[Publications] Koepsell H, Endou H.: "The SLC22 drug transporter family."Pflugers Arch.. 447. 666-676 (2004)
[Publications] 安西尚彦, 宮崎博喜, 遠藤仁: "細胞内結合タンパク質による膜輸送体機能制御Annual Review 腎臓2004、伊藤克己等編"中外医学社. 6 (2004)

2003 Fiscal Year Annual Research Report

ゲノム戦略に基づく高尿酸血症治療薬の創製

Principal Investigator

遠藤 仁 杏林大学, 医学部, 教授 (20101115)

Research Products

[Publications] Enomoto, A., Kimura, H., Chairoungdua, Okubo, M., Yamada, K., Hosoyamada, M., Shibasaki, T., Endou, H.: "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes."Toxicol.Applied Pharmacol.. 187. 162-167 (2003)

[Publications] Enomoto, A., Takeda, M., Taki, K., Takayama, F., Noshiro, R., Niwa, T., Endou, H.: "Interactions of human organic anion as well as carion transporters with indoxyl sulfate."Euro.J.Pharmacol.. 466. 13-20 (2003)

[Publications] Kanai, Y., Endou, H.: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)

[Publications] Hasegawa, M., Kusuhara, H., Endou, H., Sugiyama, Y.: "Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat."J.Pharmacol.Exp.Ther.. 305(3). 1087-1097 (2003)

[Publications] Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am J Kidney Dis.. 42(6). 1287-1292 (2003)

[Publications] Kim GH, Na KY, Kim SY, Joo KW, Oh YK, Chae SW, Endou H, Han JS.: "Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney."Nephrol Dial Transplant.. 18(8). 1505-1511 (2003)

[Publications] Yoon JH, Kim YB, Kanai Y, Endou H, Kim DK: "Sequential Increases in 4F2hc expression during DMBA-induced hamster buccal pouch cacinogenesis."Anticancer Res.. 23. 3877-3882 (2003)

[Publications] Tanaka M., Itoh K., Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am.J.Kidney Des.. 42(6). 1287-1292 (2003)

[Publications] Takeda M, Norshio R, Onozato ML, Tojo A, Hasannejad H, Hang XL, Narikawa S, Endou H.: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-GoA reductase inhibitors."Eur.J.Pharmacol.. 483. 133-138 (2004)

[Publications] Sakata T, Anzai N, Shin HJ, Norhiro R, Hirata T, Yokoyama H, Kanai Y, Endou H.: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem Biophys Res Comm.. 313. 789-793 (2004)

[Publications] Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onodera ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H.: "Interactions of human organic anion transporters with diuretics."J Pharmacol Exp Ther.. 308(3). 1021-1029 (2004)

[Publications] Khamdan S, Takeda M, Shimoda M, Noshiro Ri, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Hitoshi E: "Interactions of human- and rat-organic anion transporters with pravastatih and cimetidine."J Pharmachol sci.. 94. 197-202 (2004)

[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."Biochem Biophys Res Comm.. 94. 297-304 (2004)

[Publications] Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y.: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)

[Publications] Koepsell H, Endou H.: "The SLC22 drug transporter family."Pflugers Arch.. 447. 666-676 (2004)

[Publications] 安西尚彦, 宮崎博喜, 遠藤 仁: "細胞内結合タンパク質による膜輸送体機能制御Annual Review 腎臓2004、伊藤克己等編"中外医学社. 6 (2004)

遠藤仁杏林大学, 医学部, 教授 (20101115)

[Publications] 安西尚彦, 宮崎博喜, 遠藤仁: "細胞内結合タンパク質による膜輸送体機能制御Annual Review 腎臓2004、伊藤克己等編"中外医学社. 6 (2004)