Investigation of pathophysiological roles of transporter for antioxidant with an aim to develop pharmacotherapeutics of inflammatory organ diseases

• Project/Area Number: 24390040
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: Kato Yukio 金沢大学, 薬学系, 教授 (30251440)
• Co-Investigator(Renkei-kenkyūsha): SAKAI Yoshio 金沢大学, 医学系, 准教授 (80401925) ; WAKAYAMA Tomohiko 金沢大学, 医学系, 准教授 (70305100) ; NAKAMICHI Noritaka 金沢大学, 薬学系, 准教授 (10401895) ; SUGIURA Tomoko 金沢大学, 薬学系, 助教 (70542190)
• Research Collaborator: MASUO Yusuke 金沢大学, 薬学系, 助教 (90708140)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: 薬物動態 / 膜輸送体 / 慢性臓器疾患 / 薬物治療 / 抗酸化物質 / 薬物動態・代謝学

Outline of Final Research Achievements

The purpose of the present project is to establish the strategy to prevent and/or treat with chronic inflammatory diseases in various organs using a certain transporter which is highly expressed in the diseased lesions. Transporters are generally involved in membrane transport (influx and/or efflux) of their substrates. Therefore, transporters highly expressed in diseased lesions could be a possible target which can be used to prevent and/or treat with the corresponding diseases. This project has revealed that a certain transporter is highly expressed in diseased lesions of liver fibrosis and inflammatory bowel disease models, and that the transporter is involved in uptake of a food-derived naturally occurring antioxidant in the diseased organs, leading to suppression of deterioration of those diseases. Thus, the present findings have proposed a new strategy for pharmacotherapy of those diseases using potent antioxidant and/or thepeutic agents targeted to the transporter.

Research Products

• [Journal Article] Gene ablation of carnitine/organic cation transporter 1 reduces gastrointestinal absorption of 5-aminosalicylate in mice. (2015)
  • Author(s): Shimizu T, Kijima A, Masuo Y, Ishimoto T, Sugiura T, Takahashi S, Nakamichi N, Kato Y.
  • Journal Title: Chem Pharm Bull Volume: （印刷中）
  • NAID: 130005068086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Organic cation transporter Octn1-mediated uptake of food-derived antioxidant ergothioneine into infiltrating macrophages during intestinal inflammation in mice. (2015)
  • Author(s): Shimizu T, Masuo Y, Takahashi S, Nakamichi N and Kato Y.
  • Journal Title: Drug Metab Pharmacokinet（印刷中） Volume: （印刷中）
  • NAID: 50014429956
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased radixin function for ABC transporters in liver in adjuvant-induced arthritis rats. (2014)
  • Author(s): Kawase A, Sakata M, Yada N, Nakasaka M, Shimizu T, Kato Y, Iwaki M.
  • Journal Title: J Pharm Sci Volume: 103 Issue: 12 Pages: 4058-4065
  • DOI: 10.1002/jps.24210
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct Alterations in ABC Transporter Expression in Liver, Kidney, Small Intestine, and Brain in Adjuvant-induced Arthritic Rats. (2014)
  • Author(s): Kawase A, Norikane S, Okada A, Adachi M, Kato Y, Iwaki M.
  • Journal Title: J Pharm Sci Volume: 103 Issue: 8 Pages: 2556-2564
  • DOI: 10.1002/jps.24043
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons (2014)
  • Author(s): IshimotoT, Nakamichi N, Hosotani H, Masuo Y, Sugiura T and Kato Y.
  • Journal Title: PLoS One Volume: 9(2) Issue: 2 Pages: e89434-e89434
  • DOI: 10.1371/journal.pone.0089434
  • Peer Reviewed
• [Journal Article] Interaction of Novel Platelet-increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Human (2014)
  • Author(s): Takeuchi, et al.
  • Journal Title: Drug Metabolism and Disposition Volume: 42 Issue: 4 Pages: 726-734
  • DOI: 10.1124/dmd.113.054767
  • Peer Reviewed
• [Journal Article] Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for SN-38, an active metabolite of irinotecan, in humans (2014)
  • Author(s): Fujita K, Sasaki Y, Kato Y(他9名)
  • Journal Title: Pharm Res Volume: 31 Issue: 1 Pages: 204-15
  • DOI: 10.1007/s11095-013-1153-x
  • NAID: 120005385991
  • Peer Reviewed
• [Journal Article] Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin (2013)
  • Author(s): Nakamichi N, Shima H, Asano S, Ishimoto T, Sugiura T, Matsubara K, Kusuhara H, Sugiyama Y, Sai Y, Miyamoto KI, Tsuji A, Kato Y
  • Journal Title: J Pharm Sci Volume: 102(9) Issue: 9 Pages: 3407-3417
  • DOI: 10.1002/jps.23595
  • Peer Reviewed
• [Journal Article] Displays of paternal mouse pup retrieval following communicative interaction with maternal mates (2013)
  • Author(s): Liu, H-X., Lopatina, O., Higashida, C., Fujimoto, H., Akther, S., Inzhutova, A., Liang, M., Zhong, J., Tsuji, T., Yoshihara, T., Sumi, K., Ishiyama, M., Ma, W-J., Ozaki, M., Yagitani, S., Yokoyama, S., Mukaida, N., Sakurai, T., Hori, O., Yoshioka, K., Hirao, A., Kato, Y., Ishihara, K., Kato, I., Okamoto, H., Cherepanov, S.M., Salmina, A.B., Hirai, H., Asano, M., Brown, D.A., Nagano, I., and Higashida, H.
  • Journal Title: Nat. Commun Volume: 4 Issue: 1 Pages: 1346-1346
  • DOI: 10.1038/ncomms2336
  • Peer Reviewed
• [Journal Article] OCTN1(SLC22A4)とergothioneineの生理的役割と疾患への関与 (2013)
  • Author(s): 清水卓也、加藤将夫
  • Journal Title: 医薬のあゆみ Volume: 245(1) Pages: 36-42
• [Journal Article] Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria (2013)
  • Author(s): hitara, Y., Nakamichi, N., Norioka, M., Shima, h., Kato, Y., Horie, T
  • Journal Title: in uptake of phenformin and in mitochondria Volume: 132 Issue: 1 Pages: 32-42
  • DOI: 10.1093/toxsci/kfs330
  • Peer Reviewed
• [Journal Article] TP binding cassette transporters in two distinct compartments of skin contribute to transdermal absorption of a typical substrate (2013)
  • Author(s): Hashimoto, N., Nakamichi, N., Uwafuji, S., Yoshida, K., Sugiura, T., Tsuji, A., Kato, Y.
  • Journal Title: J. Control. Release Volume: 165 Issue: 1 Pages: 54-61
  • DOI: 10.1016/j.jconrel.2012.10.011
  • Peer Reviewed
• [Journal Article] Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans (2013)
  • Author(s): Tomoko Sugiura et al.
  • Journal Title: J. Pharm. Sci. Volume: 102(1) Issue: 1 Pages: 237-249
  • DOI: 10.1002/jps.23337
  • Peer Reviewed
• [Journal Article] Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: Possible involvement in neuronal differentiation (2012)
  • Author(s): Nakamichi, N., Taguchi, T., Hosotani, H., Wakayama, T., Shimizu, T., Sugiura, T., Iseki, S., Kato, Y
  • Journal Title: Neurochem. Int Volume: 61 Issue: 7 Pages: 1121-1132
  • DOI: 10.1016/j.neuint.2012.08.004
  • NAID: 120004966621
  • Peer Reviewed
• [Presentation] 腎疾患時における薬物動態の予測 (2014)
  • Author(s): 加藤将夫
  • Organizer: BI学会第357回研究講演会「Special Population(人種、腎疾患、肝疾患、小児)における薬物動態の予測の現状と将来展望」
  • Place of Presentation: 東京大学山上会館（東京都文京区）
  • Year and Date: 2014-12-12
  • Invited
• [Presentation] 膜輸送体OCTN1の遺伝子変異による輸送活性への影響 (2014)
  • Author(s): 二木 梓、増尾友佑、川畑志織、中道範隆、加藤将夫
  • Organizer: 第126回日本薬学会北陸支部会
  • Place of Presentation: 金沢大学角間キャンパス（石川県金沢市）
  • Year and Date: 2014-11-16
• [Presentation] Possible roles of xenobiotics transporter OCTN1/SLC22A4 in inflammatory diseases of digestive organs. (2014)
  • Author(s): 加藤将夫
  • Organizer: 上皮バリア・輸送に関するシンポジウム
  • Place of Presentation: 立命館大学BKCローム記念館（滋賀県草津市）
  • Year and Date: 2014-11-01 – 2014-11-02
  • Invited
• [Presentation] Possible interaction between carnitine/organic cation transporter OCTN1 and ERM proteins during liver fibrosis. (2014)
  • Author(s): Yu Karabayashi, Yusuke Masuo, Ryuich Harada, Noritaka Nakamichi and Yukio Kato.
  • Organizer: 上皮バリア・輸送に関するシンポジウム
  • Place of Presentation: 立命館大学BKCローム記念館（滋賀県草津市）
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] Functional characterization of organic cation transporter OCTTN1 with single nucleotide polymorphisms. (2014)
  • Author(s): Yusuke Masuo, Shiori Kawabata, Noritaka Nakamichi and Yukio Kato.
  • Organizer: 19th North American Regional ISSX Meeting and 29th JSSX Annual Meeting
  • Place of Presentation: Hilton San Francisco（米国）
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] Pharmacodynamic roles of solute carrier OCTN1/SLC22A4 for gabaergic drugs in mice. (2014)
  • Author(s): Misa Nishiyama, Noritaka Nakamichi, Yusuke Masuo and Yukio Kato.
  • Organizer: 19th North American Regional ISSX Meeting and 29th JSSX Annual Meeting
  • Place of Presentation: Hilton San Francisco（米国）
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] Functional expression of OCTN1/SLC22A4 in intestinal macrophages during gastrointestinal inflammation. (2014)
  • Author(s): Takuya Shimizu, Yusuke Masuo, Noritaka Nakamichi and Yukio Kato.
  • Organizer: 19th North American Regional ISSX Meeting and 29th JSSX Annual Meeting
  • Place of Presentation: Hilton San Francisco（米国）
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] 膜輸送タンパク質OCTN1/SLC22A4を標的とする精神神経疾患治療 (2014)
  • Author(s): 中道範隆、増尾友佑、加藤将夫
  • Organizer: 第57回日本神経化学会大会
  • Place of Presentation: 奈良県文化会館
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] 膜輸送体OCTN1の生体内基質エルゴチオネインによる神経分化促進の細胞内メカニズム (2014)
  • Author(s): 石本尚大、中道範隆、森田明希、増尾友佑、加藤将夫
  • Organizer: 第57回日本神経化学会大会
  • Place of Presentation: 奈良県文化会館（奈良県奈良市）
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] 膜輸送体OCTN1/SLC22A4を利用した炎症疾患予防と治療の可能性 (2014)
  • Author(s): 加藤将夫、増尾友佑、中道範隆
  • Organizer: 第9回遺伝子栄養学研究会学術集会
  • Place of Presentation: 札幌北広島クラッセホテル（北海道北広島市）
  • Year and Date: 2014-09-19
  • Invited
• [Presentation] 腎臓のトランスポーターについて (2014)
  • Author(s): 加藤将夫
  • Organizer: 第31回日本TDM学会・学術大会 シンポジウム「薬物トランスポーターの臓器別・包括的な機能の理解と臨床への活用を図る」
  • Place of Presentation: ソラシティカンファレンスセンター（東京都千代田区）
  • Year and Date: 2014-05-31 – 2014-06-01
  • Invited
• [Presentation] 食物由来抗酸化物質エルゴチオネインによるうつ症状軽減作用のメカニズム (2014)
  • Author(s): 石本尚大、中道範隆、中山敬悟、増尾友佑、加藤将夫
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター
• [Presentation] 膜輸送体octn1遺伝子欠損マウスの海馬におけるシナプス形成異常 (2014)
  • Author(s): 中道範隆、田中悠一、石本尚大、細谷拓史、増尾友佑、加藤将夫
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター
• [Presentation] GABA受容体作用薬の効果に及ぼす有機カチオントランスポーターOCTN1の関与 (2014)
  • Author(s): 中道範隆、西山美沙、石本尚大、増尾友佑、加藤将夫
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学黒髪キャンパス等
• [Presentation] メタボロームと薬物動態学を応用した疾患関連トランスポーターの探索 (2013)
  • Author(s): 加藤将夫
  • Organizer: 大阪大学薬学部 創薬臨床力（臨床薬理学、臨床薬物動態学、臨床薬剤学、臨床や疾患を意識した創薬科学）」にフォーカスしたシンポジウム
  • Place of Presentation: 大阪大学薬学研究科特別講義室
  • Invited
• [Presentation] 疾患関連有機カチオントランスポーターと診断・治療への応用 (2013)
  • Author(s): 加藤将夫
  • Organizer: 日本DDS学会ワークショップ「トランスポーターとDDS」
  • Place of Presentation: 京都テルサ
  • Invited
• [Presentation] マウス神経系前駆細胞において膜輸送体OCTN1を介したエルゴチオネインの取り込みは神経細胞への分化能を促進する (2013)
  • Author(s): 石本尚大、中道範隆、細谷拓史、杉浦智子、加藤将夫
  • Organizer: 第56回日本神経化学会大会
  • Place of Presentation: 国立京都国際会館
• [Presentation] NASHモデルマウスにおけるトランスポーターOCTN1の発現と局在 (2013)
  • Author(s): 増尾友佑、杉浦智子、酒井佳夫、原田龍一、若山友彦、中道範隆、井関尚一、金子周一、加藤将夫
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: タワーホール船堀
• [Presentation] OCTN1/SLC22A4の生体内基質エルゴチオネインの脳内分布と抗うつ作用 (2013)
  • Author(s): 中山敬悟、中道範隆、石本尚大、杉浦智子、増尾友佑、若山友彦、井関尚一、関口博太、須藤慶太、杉正人、宇住晃治、加藤将夫
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: タワーホール船堀
• [Presentation] キノコ由来抗酸化成分エルゴチオネインの抗うつ作用 (2013)
  • Author(s): 中道範隆、中山敬悟、石本尚大、増尾友佑、関口博太、須藤慶太、杉正人、宇住晃治、 加藤将夫
  • Organizer: 第43回日本神経精神薬理学会
  • Place of Presentation: 沖縄コンベンションセンター
• [Presentation] 脳移行性抗酸化物質エルゴチオネインの神経分化促進作用 (2013)
  • Author(s): 石本尚大、中道範隆、中山敬悟、増尾友佑、加藤将夫
  • Organizer: 日本薬学会北陸支部第125回例会
  • Place of Presentation: 北陸大学薬学部アネックスファーム
• [Presentation] 膜輸送体octn1の遺伝子欠損が神経発達関連遺伝子に及ぼす影響 (2013)
  • Author(s): 田中悠一、中道範隆、石本尚大、細谷拓史、増尾友佑、加藤将夫
  • Organizer: 日本薬学会北陸支部第125回例会
  • Place of Presentation: 北陸大学薬学部アネックスファーム
• [Presentation] 神経幹細胞に発現する膜輸送体 OCTN1 の機能と病態生理学的意義 (2013)
  • Author(s): 中道範隆、石本尚大、中山敬悟、増尾友佑、加藤将夫
  • Organizer: 第35回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 東京大学薬学系研究科
• [Presentation] Modulation of proliferation and differentiation activity by solute carrier OCTN1/SLC22A4 in neural progenitor cells (2013)
  • Author(s): Noritaka Nakamichi, Takahiro Ishimoto, Hiroshi Hosotani, Tomoko Sugiura and Yukio Kato
  • Organizer: ISN (International Society for Neurochemistry) -ASN (American Society for Neurochemistry) 2013
  • Place of Presentation: Cancun Convention Center, Cancun, Mexico
• [Presentation] 神経幹細胞における膜輸送体OCTNIの機能的発現と細胞増殖に及ぼす役割 (2013)
  • Author(s): 中道範隆
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場(福岡県)
• [Presentation] Toxicological and pathophysiological relevance of xenobiotic transporters in epithelial cells. (2012)
  • Author(s): Yukio Kato
  • Organizer: International Symposium on Epithelial Barrier and Transport 2012
  • Place of Presentation: 立命館大学(滋賀県)
• [Presentation] OCTN1/SLC22A4 is functionally expressed in hepatic non-parenchymal cells. (2012)
  • Author(s): Ryuichi Harada
  • Organizer: 18th North American Regional ISSX Meeting
  • Place of Presentation: Dallas (アメリカ合衆国)
• [Presentation] カルニチン/有機カチオントランスポーターOCTNIの肝臓での機能的発現と肝線維化に及ぼす影響 (2012)
  • Author(s): 杉浦智子
  • Organizer: 第34回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学(京都府)
• [Presentation] Association of OCTN1/SLC22A4 with activation of hepatic stellate cells (2012)
  • Author(s): 川畑志織
  • Organizer: 日本薬物動態学会第27回年会
  • Place of Presentation: タワーホール船堀(東京都)
• [Presentation] タモギタケエキス末含有成分エルゴチオネインは神経新生を促し抗うつ作用を示す
  • Author(s): 中道範隆、中山敬悟、石本尚大、増尾友佑、関口博太、須藤慶太、杉正人、宇住晃治、加藤将夫
  • Organizer: 第８回遺伝子栄養学研究会学術集会
  • Place of Presentation: 北広島クラッセホテル
• [Remarks] 分子薬物治療学研究室
  • URL: http://www.p.kanazawa-u.ac.jp/~bunyaku/
• [Remarks] 分子薬物治療学研究室
  • URL: http://www.p.kanazawa-u.ac.jp/~bunyaku/
• [Remarks]
  • URL: http://www.p.kanazawa-u.ac.jp/~bunyaku/
• [Patent(Industrial Property Rights)] 抗うつ剤 (2013)
  • Inventor(s): 加藤将夫、中道範隆、杉浦智子、谷口徳之
  • Industrial Property Rights Holder: 金沢大学
  • Industrial Property Number: 2013-039228
  • Filing Date: 2013-02-28