Studies searching for functional food components to control novel SUA regulators

• Project/Area Number: 16H01808
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Eating habits
• Research Institution: The University of Tokyo
• Principal Investigator: TAKADA Tappei 東京大学, 医学部附属病院, 講師 (90376468)
• Co-Investigator(Kenkyū-buntansha): 松尾 洋孝 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 分子生体制御学, 准教授 (00528292) ; 井上 勝央 東京薬科大学, 薬学部, 教授 (50315892) ; 薩 秀夫 前橋工科大学, 工学部, 准教授 (80323484)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥40,170,000 (Direct Cost: ¥30,900,000、Indirect Cost: ¥9,270,000); Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2018: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2017: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2016: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
• Keywords: 栄養学 / 生理学 / トランスレーショナルリサーチ / トランスポーター / 尿酸 / ABCG2 / OAT10 / ゲノム

Outline of Final Research Achievements

By in vitro and in vivo experiments and clinical analyses, we revealed that 1) OAT10/SLC22A13 mediates physiological transport of urate and its dysfunctional missense variant (R377C) decreases gout risk and serum uric acid levels, 2) ABCG2 is a physiological exporter of uremic toxin indoxyl sulfate and a crucial factor influencing CKD progression, 3) some of antihyperuricemic drugs such as febuxostat are strong ABCG2 inhibitors, and osthol isolated from Cnidium monnieri fruit and flavonoids in Citrus fruits have potential to inhibit URAT1-mediated transport of urate.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた研究成果は、痛風、高尿酸血症、慢性腎不全などのさまざまな疾患の予防・治療戦略の立案に役立つことが期待される。具体的には、遺伝子診断による各種疾患のリスク予測、より効果の強い尿酸降下薬の創製、尿酸排泄促進作用を有する機能性食品の開発などに貢献しうるものと考えられ、応用研究も含め、今後の研究のさらなる発展が待たれる。

Research Products

• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Int'l Joint Research] University of Otago(ニュージーランド)
• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Int'l Joint Research] University of Otago/University of Auckland(New Zealand)
• [Journal Article] Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients. (2020)
  • Author(s): Nakayama A, Takada T, et al.
  • Journal Title: Ann Rheum Dis. Volume: 79 Issue: 5 Pages: 657665-657665
  • DOI: 10.1136/annrheumdis-2019-216644
  • NAID: 120007042436
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients (2020)
  • Author(s): Nakashima Akio、Ichida Kimiyoshi、Ohkido Ichiro、Yokoyama Keitaro、Matsuo Hirotaka、Ohashi Yuki、Takada Tappei、Nakayama Akiyoshi、Suzuki Hiroshi、Shinomiya Nariyoshi、Urashima Mitsuyoshi、Yokoo Takashi
  • Journal Title: Human Cell Volume: epub ahead of print Issue: 3 Pages: 1-10
  • DOI: 10.1007/s13577-020-00342-w
  • Peer Reviewed / Open Access
• [Journal Article] A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population. (2020)
  • Author(s): Akashi A, Nakayama A, Kamatani Y, Higashino T, Shimizu S, Kawamura Y, Imoto M, Naito M, Hishida A, Kawaguchi M, Takao M, Matsuo M, Takada T, Ichida K, Ooyama H, Shinomiya N, Matsuo H.
  • Journal Title: Hum Cell. Volume: 33 Issue: 2 Pages: 303307-303307
  • DOI: 10.1007/s13577-019-00318-5
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of Citrus flavonoids on the in vitro transport activity of human urate transporter 1 (URAT1/SLC22A12), a renal re-absorber of urate. (2020)
  • Author(s): Toyoda Y, Takada T, Saito H, Hirata H, Ota-Kontani A, Kobayashi N, Tsuchiya Y, Suzuki H.
  • Journal Title: NPJ Sci Food. Volume: 4 Issue: 1 Pages: 3-3
  • DOI: 10.1038/s41538-020-0063-7
  • Peer Reviewed / Open Access
• [Journal Article] Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. (2020)
  • Author(s): Higashino T, Morimoto K, Nakaoka H, Toyoda Y, Kawamura Y, Shimizu S, Nakamura T, Hosomichi K, Nakayama A, Ooyama K, Ooyama H, Shimizu T, Ueno M, Ito T, Tamura T, Naito M, Nakashima H, Kawaguchi M, Takao M, Kawai Y, Osada N, Ichida K, Yamamoto K, Suzuki H, Shinomiya N, Inoue I, Takada T, Matsuo H.
  • Journal Title: Ann Rheum Dis. Volume: 79(1) Issue: 1 Pages: 164-166
  • DOI: 10.1136/annrheumdis-2019-216044
  • Peer Reviewed / Open Access
• [Journal Article] Familial early-onset hyperuricemia and gout associated with a newly identified dysfunctional variant in urate transporter ABCG2. (2019)
  • Author(s): Toyoda Y, Pavelcova K, Klein M, Suzuki H, Takada T, Stiburkova B.
  • Journal Title: Arthritis Res Ther. Volume: 21(1) Issue: 1 Pages: 219-219
  • DOI: 10.1186/s13075-019-2007-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout (2019)
  • Author(s): Kawamura Y, Nakaoka H, Nakayama A, et al.
  • Journal Title: Ann Rheum Dis Volume: 78 Issue: 10 Pages: 1430-1437
  • DOI: 10.1136/annrheumdis-2019-215521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort (2019)
  • Author(s): Toyoda Yu, Mancikova Andrea, Krylov Vladimir, Morimoto Keito, Pavelcova Katerina, Bohata Jona, Pavelka Karel, Pavlikova Marketa, Suzuki Hiroshi, Matsuo Hirotaka, Takada Tappei, Stiburkova Blanka
  • Journal Title: Cells Volume: 8 Issue: 4 Pages: 363-363
  • DOI: 10.3390/cells8040363
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications. (2019)
  • Author(s): Toyoda Y, Takada T, Suzuki H.
  • Journal Title: Front Pharmacol. Volume: 10 Pages: 208-208
  • DOI: 10.3389/fphar.2019.00208
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Osthol Isolated from Cnidium monnieri Fruit on Urate Transporter 1. (2018)
  • Author(s): Tashiro Y, Sakai R, Hirose-Sugiura T, Kato Y, Matsuo H, Takada T, Suzuki H, Makino T.
  • Journal Title: Molecules. Volume: 23(11) Issue: 11 Pages: 2837-2837
  • DOI: 10.3390/molecules23112837
  • Peer Reviewed / Open Access
• [Journal Article] Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression. (2018)
  • Author(s): Takada T, Yamamoto T, Matsuo H, Tan JK, Ooyama K, Sakiyama M, Miyata H, Yamanashi Y, Toyoda Y, Higashino T, Nakayama A, Nakashima A, Shinomiya N, Ichida K, Ooyama H, Fujimori S, Suzuki H
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11147-11147
  • DOI: 10.1038/s41598-018-29208-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of the transport of xanthine dehydrogenase inhibitors by the urate transporter ABCG2 (2018)
  • Author(s): Nakamura Makiko、Fujita Kyoko、Toyoda Yu、Takada Tappei、Hasegawa Hiroshi、Ichida Kimiyoshi
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 33 Issue: 1 Pages: 77-81
  • DOI: 10.1016/j.dmpk.2017.11.002
  • NAID: 210000186733
  • Peer Reviewed / Open Access
• [Journal Article] Multiple common and rare variants of ABCG2 cause gout (2017)
  • Author(s): Higashino Toshihide、Takada Tappei、Nakaoka Hirofumi、Toyoda Yu、Stiburkova Blanka、Miyata Hiroshi、Ikebuchi Yuki、Nakashima Hiroshi、Shimizu Seiko、Kawaguchi Makoto、Sakiyama Masayuki、Nakayama Akiyoshi、Akashi Airi、Tanahashi Yuki、Kawamura Yusuke、Nakamura Takahiro、Wakai Kenji、Hosomichi Kazuyoshi 他
  • Journal Title: RMD Open Volume: 3 Issue: 2 Pages: e000464-e000464
  • DOI: 10.1136/rmdopen-2017-000464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes (2017)
  • Author(s): Nakayama A, Nakaoka H, Yamamoto K, Sakiyama M, Shaukat A, Toyoda Y, Okada Y, Ohkawa Y,他39名
  • Journal Title: Ann Rheum Dis. Volume: 76 Issue: 5 Pages: 869
  • DOI: 10.1136/annrheumdis-2016-209632
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations. (2016)
  • Author(s): Miyata H*, Takada T*, Toyoda Y*, Matsuo H, Ichida K, Suzuki H.
  • Journal Title: Front Pharmacol. Volume: 7 Pages: 518-518
  • DOI: 10.3389/fphar.2016.00518
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immunohistochemical and in situ hybridization study of urate transporters GLUT9/URATv1, ABCG2, and URAT1 in the murine brain. (2016)
  • Author(s): Tomioka NH, et al.
  • Journal Title: Fluids Barriers CNS. Volume: 13 Pages: 22-22
  • Peer Reviewed / Open Access
• [Journal Article] Common variant of PDZ domain containing 1 (PDZK1) gene is associated with gout susceptibility: A replication study and meta-analysis in Japanese population. (2016)
  • Author(s): Higashino T, et al.
  • Journal Title: Drug Metab Pharmacokinet. Volume: 31 Issue: 6 Pages: 464-466
  • DOI: 10.1016/j.dmpk.2016.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2. (2016)
  • Author(s): Matsuo H, et al.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 31003-31003
  • DOI: 10.1038/srep31003
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. (2015)
  • Author(s): Matsuo H, et al.
  • Journal Title: Ann Rheum Dis. Volume: 印刷中 Issue: 4 Pages: 652-659
  • DOI: 10.1136/annrheumdis-2014-206191
  • Peer Reviewed / Open Access
• [Presentation] ABCG2, a physiologically and pharmacologically important exporter in humans (2020)
  • Author(s): Tappei Takada, et al.
  • Organizer: 8th FEBS Special Meeting: ABC Proteins - from Genetic Disease to Multidrug Resistance
  • Int'l Joint Research / Invited
• [Presentation] 尿酸排出トランスポーターによる尿酸動態制御メカニズムの解析 (2020)
  • Author(s): 高田龍平
  • Organizer: 第53回日本痛風・尿酸核酸学会総会
  • Invited
• [Presentation] ABCG2 transports urate and uremic toxin indoxyl sulfate and influences CKD progression (2019)
  • Author(s): Tappei Takada, et al.
  • Organizer: Asia-Pacific Gout Consortium 3rd Annual Meeting (APGC 2019)
  • Int'l Joint Research / Invited
• [Presentation] Urate transporter ABCG2 is a physiological exporter of uremic toxin indoxyl sulfate and a crucial factor influencing CKD progression (2019)
  • Author(s): Tappei Takada, et al.
  • Organizer: 18th International Symposium on Purine and Pyrimidine Metabolism in Man
  • Int'l Joint Research / Invited
• [Presentation] 腸管・腎尿細管の尿酸輸送と高尿酸血症 (2019)
  • Author(s): 高田龍平、他
  • Organizer: 第50回日本消化吸収学会総会
  • Invited
• [Presentation] 尿酸排出トランスポーターABCG2に関する生理学的・薬理学的研究 (2019)
  • Author(s): 高田龍平、他
  • Organizer: 生理研研究会『上皮膜・間質の機能連関と病態発現機構解明のためのストラテジー』
  • Invited
• [Presentation] 微粒子形成の予防～尿酸動態制御と薬物治療について～ (2019)
  • Author(s): 高田龍平、他
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] Molecular functional analyses of transporters related to "urate transport disorders" (2018)
  • Author(s): Tappei Takada, et al.
  • Organizer: Joint Conference of the 2nd Asia-Pacific Gout Consortium (APGC) and the 8th Oriental Gout Forum
  • Int'l Joint Research / Invited
• [Presentation] Pathophysiological metabolome analysis of ABCG2 transporter (2018)
  • Author(s): Tappei Takada, et al.
  • Organizer: International Meeting on 22nd MDO and 33rd JSSX
  • Int'l Joint Research / Invited
• [Presentation] Reverse translational research on membrane transporters (2018)
  • Author(s): Tappei Takada
  • Organizer: 18th World Congress of basic and clinical Pharmacology (WCP2018)
  • Int'l Joint Research / Invited
• [Presentation] 生活習慣病とトランスポーターに関する研究～病院薬剤師の視点から～ (2018)
  • Author(s): 高田龍平
  • Organizer: 第7回 BRIGHT symposium
  • Invited
• [Presentation] 血清尿酸値変動薬と尿酸排出トランスポーターABCG2の相互作用に関する研究 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 第40回生体膜と薬物の相互作用シンポジウム
• [Presentation] 尿酸排出輸送体ABCG2による尿酸動態制御機構の解明 (2018)
  • Author(s): 高田龍平
  • Organizer: 第29回痛風研修会
  • Invited
• [Presentation] 尿酸排出トランスポーターABCG2による血清尿酸値制御 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 生理研研究会『体内環境の維持機構における上皮膜輸送の多角的・統合的理解』
  • Invited
• [Presentation] 尿毒素輸送体と腎疾患 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] 血清尿酸値変動薬が尿酸輸送体ABCG2に与える影響の検討 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 第51回日本痛風・核酸代謝学会総会
• [Presentation] Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations (2017)
  • Author(s): Yu Toyoda, Tappei Takada, Hiroshi Miyata, Hirotaka Matsuo, Kimiyoshi Ichida, Hiroshi Suzuki
  • Organizer: Gordon Research Seminar: Multi-Drug Efflux Systems
  • Place of Presentation: Galveston（USA）
  • Year and Date: 2017-03-25
  • Int'l Joint Research
• [Presentation] トランスポーターのリバーストランスレーショナルリサーチ (2017)
  • Author(s): 高田龍平、山梨義英、豊田優、鈴木洋史
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター、他（宮城県仙台市）
  • Year and Date: 2017-03-24
• [Presentation] トランスポーターによる生活習慣病関連物質輸送と病態～脂溶性ビタミンと尿酸について～ (2017)
  • Author(s): 高田龍平
  • Organizer: 第3回炎症・生体防御研究セミナー
  • Place of Presentation: 日亜ホールWhite（徳島県徳島市）
  • Year and Date: 2017-02-23
  • Invited
• [Presentation] 尿酸低下を目指した薬物療法と問題点 (2017)
  • Author(s): 高田龍平
  • Organizer: 第50回日本痛風・核酸代謝学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2017-02-16
• [Presentation] ABCG2-mediated drug interaction risks with febuxostat medication (2017)
  • Author(s): Tappei Takada, et al.
  • Organizer: 17th International Symposium on Purine and Pyrimidine Metabolism in Man
  • Int'l Joint Research / Invited
• [Presentation] Urate transporter ABCG2-mediated drug-drug interaction risks during febuxostat medication (2017)
  • Author(s): Tappei Takada
  • Organizer: Asia-Pacific Gout Consortium (APGC)
  • Int'l Joint Research / Invited
• [Presentation] 膜輸送体ABCG2/BCRPによる尿酸輸送と高尿酸血症・痛風 (2016)
  • Author(s): 高田龍平、松尾洋孝、市田公美、鈴木洋史
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター、他（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 遺伝子研究からわかってきた痛風・高尿酸血症の病態と新規病型分類 (2016)
  • Author(s): 高田龍平
  • Organizer: 糖尿病フォーラム2016 in 仙台
  • Place of Presentation: ウェスティンホテル仙台（宮城県仙台市）
  • Year and Date: 2016-07-29
  • Invited
• [Book] 痛風と核酸代謝（血清尿酸値変動薬が尿酸輸送体ABCG2に与える影響の検討） (2018)
  • Author(s): 高田龍平、松尾洋孝、市田公美
  • Total Pages: 2
  • Publisher: 日本痛風・核酸代謝学会
• [Book] 痛風と核酸代謝（尿酸トランスポーター遺伝子ABCG2のレアバリアントはコモンバリアントと同様に痛風のリスクを著しく上昇させる） (2018)
  • Author(s): 松尾洋孝、東野俊英、高田龍平、清水聖子、川口真、崎山真幸、中山昌喜、河村優輔、細谷龍男、市田公美、大山博司、鈴木洋史、四ノ宮成祥
  • Total Pages: 1
  • Publisher: 日本痛風・核酸代謝学会
• [Book] 痛風と核酸代謝（CKD患者の腎機能低下に及ぼす尿酸トランスポーターABCG2の保護的役割の解明） (2018)
  • Author(s): 三輪裕幸、内田俊也、柴田茂、高田龍平、松尾洋孝、市田公美
  • Total Pages: 1
  • Publisher: 日本痛風・核酸代謝学会
• [Book] 痛風と核酸代謝（尿酸低下を目指した薬物療法と問題点） (2017)
  • Author(s): 高田龍平
  • Total Pages: 1
  • Publisher: 日本痛風・核酸代謝学会
• [Remarks] 自己紹介（研究室ホームページ内）
  • URL: http://plaza.umin.ac.jp/~todaiyak/t_takada.php