Development of individualized drug therapy based on the regulation of drug metabolism and transport proteins by uremic toxins

• Project/Area Number: 23790187
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: WATANABE Hiroshi 熊本大学, 薬学部, 准教授 (70398220)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 尿毒症物質 / 薬物動態制御タンパク質 / PTH / インドキシル硫酸

Research Abstract

We investigated the effect of uremic toxins on protein expression of hepaticdrug metabolizing enzymes. As a results, IS, PCS and CMPF increased the expression of CYP2E1 andSUL T1A1, and intact PTH also increased SUL T1A1 in dose-dependent manner . Next we examined theeffect of PCS on renal tubular toxicity . Intracellular accumulation of PCS via OA Ts in renal tubular cellsenhanced NADPH oxidase activity and increased ROS production. This, in turn, triggers the inductionof inflammatory cytokines that are involved in renal toxicity .

Research Products

• [Journal Article] Long-acting human serumalbumin-thioredoxin fusion proteinsuppresses bleomycin-inducedpulmonary fibrosis progression (2013)
  • Author(s): Tanaka R, Watanabe H, Kodama A, ChuangVT, Ishima Y, Hamasaki K, Tanaka KI,Mizushima T, Otagiri M, Maruyama T
  • Journal Title: JPharmacol Exp Ther Volume: 345 Pages: 271-283
  • Peer Reviewed
• [Journal Article] p-Cresylsulfate causes renal tubular celldamage by inducing oxidative stressthrough the activation of NADPHoxidase (2013)
  • Author(s): Watanabe H, Miyamoto M, Honda D, TanakaH, Wu Q, Endo M, Noguchi T, Kadowaki D,Ishima Y, Kotani S, Nakajima M, KataokaK, Kim-Mitsuyama S, Tanaka M, FukagawaM, Otagiri M, Maruyama M
  • Journal Title: Kidney Int Volume: 83 Pages: 582-592
  • Peer Reviewed
• [Journal Article] A human serumalbumin-thioredoxin fusion proteinprevents experimentalcontrast-induced nephropathy (2013)
  • Author(s): Kodama A, Watanabe H, Tanaka R, TanakaH, Chuang VTG, Miyamoto Y, Wu Q, EndoM, Hamasaki K, Ishima Y, Fukagawa M, Otagiri M, Maruyama T
  • Journal Title: KidneyInt Volume: 83 Pages: 446-454
  • Peer Reviewed
• [Journal Article] p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress byactivation of NADPH oxidase. (2013)
  • Author(s): Hiroshi Watanabe^*, Yohei Miyamoto^*,Daisuke Honda, Hisae Tariaka, Qiong Wu,Masayuki Endo, Tsuyoshi Noguchi, DaisukeKadowaki, Yu Ishima, Shunsuke Kotani,Makoto Nakajima, Keiichiro Kataoka,Shokei Kim-Mitsuyama, Motoko Tanaka,Masafumi Fukagawa, Masaki Otagiri, ToruMaruyama. (^*:Hiroshi Watanabe and YoheiMiyamoto contributed equally to this work.)
  • Journal Title: Kidney International Volume: (印刷中) Issue: 4 Pages: 582-592
  • DOI: 10.1038/ki.2012.448
  • Peer Reviewed
• [Journal Article] A human serum albumin-thioredoxin fusion protein prevents experimental contrast-induced nephropathy. (2013)
  • Author(s): Kodama A
  • Journal Title: Kidney Int. Volume: 印刷中 Issue: 3 Pages: 446-54
  • DOI: 10.1038/ki.2012.429
  • Peer Reviewed
• [Journal Article] Interaction between two sulfate-conjugated uremic toxins, p-cresyl sulfate and indoxyl sulfate, during binding with human serum albumin. (2013)
  • Author(s): Watanabe H
  • Journal Title: Biochim Biophys Acta. Volume: 40 Issue: 7 Pages: 1423-8
  • DOI: 10.1124/dmd.112.045617
  • Peer Reviewed
• [Journal Article] A uremictoxin,3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage toproximal tubular cells via thegeneration of a radical intermediate (2012)
  • Author(s): Miyamoto Y, Iwao Y, Mera K, WatanabeH, Kadowaki D, Ishima Y, Chuang VT,Sato K, Otagiri M, Maruyama T
  • Journal Title: Biochem Pharmacol Volume: 84 Pages: 1207-1214
  • Peer Reviewed
• [Journal Article] α_1-Acid glycoproteinup-regulates CD163 via TLR4/CD14pathway: Possible protection againsthemolysis-induced oxidative stress (2012)
  • Author(s): Komori H, Watanabe H, Shuto T, KodamaA, Maeda H, Watanabe K, Kai H, OtagiriM, Maruyama T
  • Journal Title: Jbiol Chem Volume: 31 Pages: 30688-30700
  • Peer Reviewed
• [Journal Article] Interaction between twosulfate conjugated uremic toxins,p-cresyl sulfate and indoxyl sulfate,during binding with human serumalbumin (2012)
  • Author(s): Watanabe H, Noguchi T, Miyamoto Y,Kadowaki D, Kotani S, Nakajima M,Miyamura S, Ishima Y, Otagiri M,Maruyama T
  • Journal Title: Drug Metab Dispos Volume: 40 Pages: 1423-1428
  • Peer Reviewed
• [Journal Article] Characterization ofhepatic cellular uptake of α1-acidglycoprotein (AGP), part 2:Involvement of hemoglobin β-chain onplasma membranes in the uptake ofhuman AGP by liver parenchymal cells (2012)
  • Author(s): Komori H, Nishi K, Uehara N, WatanabeH, Shuto T, Suenaga A, Maruyama T,Otagiri M
  • Journal Title: J Pharm Sci Volume: 101 Pages: 1607-1615
  • Peer Reviewed
• [Journal Article] Characterization of the hepaticcellular uptake of α(1) -acidglycoprotein (AGP), part 1: A peptidemoiety of human AGP is recognized bythe hemoglobin β-chain on mouse liverparenchymal cells (2012)
  • Author(s): Nishi K, Komori H, Kikuchi M, UeharaN, Fukunaga N, Matsumoto K, WatanabeH, Nakajou K, Misumi S, Suenaga A,Maruyama T, Otagiri M
  • Journal Title: J Pharm Sci Volume: 101 Pages: 1599-1606
  • Peer Reviewed
• [Journal Article] A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate. (2012)
  • Author(s): Yohei Miyamoto, Yasunori Katsumi Mera, Hiroshi Watanabe, Daisuke Kadowaki, Yu Ishima, Victor Tuan Giam Chuang, Keizo Sato, Masaki Otagiri, Toru Maruyama.
  • Journal Title: Biochemical Pharmacology Volume: 84 Issue: 9 Pages: 1207-1214
  • DOI: 10.1016/j.bcp.2012.07.033
  • Peer Reviewed
• [Journal Article] Human serumalbumin-thioredoxin fusion protein with long blood retention property iseffective in suppressing lung injury (2011)
  • Author(s): Furukawa M, Tanaka R, Chuang VTG,Ishima Y, Taguchi K, Watanabe H,Maruyama T, Otagiri M
  • Journal Title: J Control Release Volume: 154 Pages: 189-154
  • Peer Reviewed
• [Journal Article] CYS34 on antioxidativepropertie of HSA quantitativeanalysis of cysteine-34 on theanitioxidative properties of humanserum albumin in hemodialysispatients (2011)
  • Author(s): Anraku M, Takeuchi K, Watanabe H,Kadowaki D, Kitamura K, Tomita K,Kuniyasu A, Suenaga A, Maruyama T,Otagiri M
  • Journal Title: J Pharm Sci Volume: 100 Pages: 3968-3976
  • Peer Reviewed
• [Journal Article] Structural insights intodifferences in drug bindingselectivity between two forms of humanalpha1-acid glycoprotein geneticvariants, the A and F1*S forms (2011)
  • Author(s): Nishi K, Ono T, Nakamura T, FukunagaN, Izumi M, Watanabe H, Suenaga A,Maruyama T, Yamagata Y, Curry S,Otagiri M
  • Journal Title: JBiol Chem Volume: 286 Pages: 14427-14434
  • Peer Reviewed
• [Journal Article] Organic aniontransporters play an important role inthe uptake of p-cresyl sulfate, auremic toxin, in the kidney (2011)
  • Author(s): Miyamoto Y, Watanabe H, Noguchi T,Kotani S, Nakajima M, Kadowaki D,Otagiri M, Maruyama T
  • Journal Title: Nephrol Dial Transplant Volume: 26 Pages: 2498-2502
  • Peer Reviewed
• [Presentation] 尿毒症物質 p-クレジル硫酸は OATsを介して近位尿細管上皮、血管内皮及び血管平滑筋細胞に取り込まれ酸化ストレス障害を誘発する (2012)
  • Author(s): 渡邊博志,宮本洋平,本田大輔,田中寿絵,深川雅史,異島優,小田切優樹,丸山徹
  • 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(千葉)
  • Year and Date: 2012-11-20
• [Presentation] 尿毒症物質 p-クレジル硫酸のレドックス特性と腎障害、心血管疾患発症機序解明 (2012)
  • Author(s): 宮本洋平,渡邊博志,本田大輔,門脇大介,異島優,深川雅史,小田切優樹,丸山徹
  • 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)
  • Year and Date: 2012-11-15
• [Presentation] p-Cresyl sulfate causesrenal tubular cell damage by inducingoxidative stress through theactivation of NADPH oxidase (2012)
  • Author(s): Hiroshi Watanabe, Daisuke Honda,Yohei Miyamoto, Tsuyoshi Noguchi,Daisuke Kadowaki, Yu Ishima, MotokoTanaka, Hisae Tanaka, MasafumiFukagawa, Masaki Otagiri and Toru Maruyama
  • Organizer: 49th ERA-EDTA Congress, Paris 2012
  • Place of Presentation: Paris (France)
  • Year and Date: 2012-05-24
• [Presentation] A uremictoxin, CMPF accumulates in proximaltubular cells and induces cell damagethrough increasing oxidative stress (2012)
  • Author(s): Yohei Miyamoto, Yasunori Iwao,Katsumi Mera, Hiroshi Watanabe,Daisuke Kadowaki, Yu Ishima1, VictorTuan Giam Chuang, Keizo Sato, MasakiOtagiri and Toru Maruyama
  • Organizer: 49th ERA-EDTA Congress, Paris 2012
  • Place of Presentation: Paris (France)
  • Year and Date: 2012-05-24
• [Presentation] 尿毒症物質, p-クレジル硫酸の酸化ストレス誘導を介した腎障害作用 (2012)
  • Author(s): 渡邊博志, 本田大輔, 宮本洋平, 野口剛,門脇大介,異島優,小谷俊介,中島誠,深川雅史,小田切優樹,丸山徹
  • Organizer: 日本薬学会第132 年会
  • Place of Presentation: 北海道大学 (北海道)
  • Year and Date: 2012-03-28
• [Presentation] p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress through the activation of NADPH oxidase (2012)
  • Author(s): Hiroshi Watanabe, Daisuke Honda, Yohei Miyamoto, Tsuyoshi Noguchi, Daisuke Kadowaki, Yu Ishima, Motoko Tanaka, Hisae Tanaka, Masafumi Fukagawa, Masaki Otagiri and Toru Maruyama
  • Organizer: 49th ERA-EDTA Congress, Paris 2012
  • Place of Presentation: Paris（フランス）
• [Presentation] A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate accumulates in proximal tubular cells and induces cell damage through increasing oxidative stress (2012)
  • Author(s): Yohei Miyamoto, Yasunori Iwao, Katsumi Mera, Hiroshi Watanabe, Daisuke Kadowaki, Yu Ishima, Victor Tuan Giam Chuang, Keizo Sato, Masaki Otagiri and Toru Maruyama
  • Organizer: 49th ERA-EDTA Congress, Paris 2012
  • Place of Presentation: Paris（フランス）
• [Presentation] 尿毒症物質p-クレジル硫酸のレドックス特性と腎障害、心血管疾患発症機序解明 (2012)
  • Author(s): 宮本洋平、渡邊博志、本田大輔、門脇大介、異島優、深川雅史、小田切優樹、丸山徹
  • Organizer: 第34回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学薬学部
• [Presentation] ヒト血清アルブミン－チオレドキシン融合タンパク質は抗酸化作用によりシスプラチン誘発腎障害を抑制する (2012)
  • Author(s): 小玉 あずさ, 田中 遼大, 渡邊 博志, 異島 優, 小田切 優樹, 丸山 徹
  • 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
• [Presentation] 尿毒症物質p-クレジル硫酸はOATsを介して近位尿細管上皮、血管内皮及び血管平滑筋細胞に取り込まれ酸化ストレス障害を誘発する (2012)
  • Author(s): 渡邊博志、宮本洋平、本田大輔、田中寿絵、深川雅史、異島優、小田切優樹、丸山徹
  • 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
• [Presentation] 急性腎障害に対するアルブミン-チオレドキシン融合体の治療効果と機序解明 (2012)
  • Author(s): 小玉 あずさ、田中 遼大、渡邊 博志、田中 寿絵、異島 優、深川 雅史、小田切 優樹、丸山 徹
  • Organizer: 第29回 日本薬学会九州支部大会
  • Place of Presentation: 熊本大学薬学部
• [Presentation] 尿毒症物質はインドキシル硫酸の生合成を促進する (2011)
  • Author(s): 村田道哉,児玉彬,渡邊博志,異島優,小田切優樹,丸山徹
  • Organizer: 第28回日本薬学会九州支部大会
  • Place of Presentation: 福岡大学薬学部(福岡)
  • Year and Date: 2011-12-10
• [Presentation] Interaction betweenp-cresol sulfate and indoxyl sulfateduring body disposition can influencetheir serum free concntrations inchronic kidney disease (2011)
  • Author(s): Watanabe H, Miyamoto Y, Noguchi T,Suenaga A, Kadowaki D, Otagiri M,Maruyama T
  • Organizer: AsianFederation For PharmaceuticalSciences Conference
  • Place of Presentation: KualaLumpur (Malaysia)
  • Year and Date: 2011-12-09
• [Presentation] 尿毒症物質 p-クレジル硫酸とインドキシル硫酸との相互作用の動態学的機序解明 (2011)
  • Author(s): 野口剛,宮本洋平,渡邊博志,小田切優樹,丸山徹
  • Organizer: 日本薬剤学会 26 年会
  • Place of Presentation: タワーホール船堀(千葉)
  • Year and Date: 2011-05-29
• [Presentation] 尿毒症物質p-クレジル硫酸が慢性腎臓病の酸化ストレスに及ぼす影響 (2011)
  • Author(s): 本田大輔, 宮本洋平, 渡邊博志, 門脇大介, 小田切優樹, 丸山徹
  • Organizer: 日本薬剤学会 26年会
  • Place of Presentation: タワーホール船堀(千葉)
  • Year and Date: 2011-05-29
• [Presentation] CMPF causes renal cell damage viaoxidative stress induction (2011)
  • Author(s): Yohei Miyamoto, Yasunori Iwao,Katsumi Mera, Hiroshi Watanabe,Daisuke Kadowaki Keizo Sato, MasakiOtagiri, Toru Maruyama, Uremic toxin
  • Organizer: 7th International Congress on UremiaResearch and Toxicity 2011
  • Place of Presentation: Nagoya Congress Center (Nagoya)
  • Year and Date: 2011-05-12
• [Presentation] The uremic solute indoxyl sulfate acts as an antioxidant against superoxide anion radicals under normal-physiological conditions (2011)
  • Author(s): Yohei Miyamoto, Yasunori Iwao, YukaTasaki, Keizo Sato, Yu Ishima, HiroshiWatanabe, Daisuke Kadowaki, ToruMaruyama and Masaki Otagiri
  • Organizer: 4^th Asia Pacific ISSX Meeting 2011
  • Place of Presentation: Tainan (Taiwan)
  • Year and Date: 2011-04-22
• [Presentation] 尿毒症物質はインドキシル硫酸の生合成を促進する (2011)
  • Author(s): 村田 道哉、児玉 彬、渡邊 博志、異島 優、小田切 優樹、丸山 徹
  • Organizer: 第28回日本薬学会九州支部大会
  • Place of Presentation: 福岡大学
• [Remarks]
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/Yakuzai/