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Mechanism of expression and function of drug transporters in endotoxemia

Research Project

Project/Area Number 20590587
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory medicine
Research InstitutionAichi Medical University

Principal Investigator

HASEGAWA Takaaki  Aichi Medical University, 医学部, 教授 (80198720)

Co-Investigator(Kenkyū-buntansha) FENG GuoーGang  愛知医科大学, 医学部, 講師 (70351111)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2008: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywordsエンドトキシン / トランスポーター / サイトカイン / 生体膜輸送 / 薬物トランスポーター / 胆汁排泄 / ミカファンギン / 有機アニオン輸送系 / 尿細管分泌 / パラアミノ馬尿酸 / Bcrp / CYP3A2 / IL-6
Research Abstract

Firstly, the effect of endotoxin (ET) on the function and expression of hepatic breast cancer resistance protein (Bcrp) was investigated in mice. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased 24 h after ET injection. Both Western blot and immunofluorescence analyses also revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of ET. ET significantly induced the overproduction of the cytokines IL-6 and IL-1β. Pretreatment with IL-6 significantly decreased the CL_<BILE> of mitoxantrone. Hepatic Bcrp was significantly down-regulated by injection of IL-6 (50,000U/mouse). These findings suggest that ET reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is likely due to increased IL-6 levels. Secondly, to clarify ET-induced changes in organic anion transport ability, GFR and renal tubular secretion clearance of PAH which is a substrate for renal organic anion transporter 1 (Oat1) and Oat3 were investigated in endotoxemic rats. The expression of Oat1 and Oat3 mRNA was decreased, and the expression returned to control levels after 72 h after injection of ET. These findings suggest that the decreased mRNA levels of renal Oat1 and Oat3 are involved in the decreased renal tubular secretion clearance of PAH in endotoxemic rats and that these changes are transient and recovered time-dependently.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (51 results)

All 2011 2010 2009 2008 Other

All Journal Article (44 results) (of which Peer Reviewed: 44 results) Book (6 results) Remarks (1 results)

  • [Journal Article] Involvement of sulfate conjugation and multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of garenoxacin in rats.2011

    • Author(s)
      Hayashi T, Abe F, Kato M, Saito H, Ueyama J, Kondo Y, Imai Y, Katoh M, Nadai M, Hasegawa T
    • Journal Title

      J.Infect. Chemother. 17

      Pages: 24-28

    • NAID

      10027816638

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Endotoxin does not alter the pharmacokinetics of micafungin, but it impairs biliary excretion of micafungin via multidrug resistance associated protein 2 (ABCC2/Mrp2) in rats.2011

    • Author(s)
      Noda T, Abe F, Ueyama J, Kato M, Katoh M, Nadai M, Saito H, Hasegawa T
    • Journal Title

      J.Infect. Chemother. 17

      Pages: 207-213

    • NAID

      10028171423

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of sulfate conjugation and multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of garenoxacin in rats2011

    • Author(s)
      Tamon Hayashi
    • Journal Title

      J.Infect.Chemother.

      Volume: VOL.17 Pages: 24-29

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endotoxin does not alter the pharmacokinetics of micafungin, but it impairs biliary excretion of micafungin via multidrug resistance-associated protein 2 (ABCC2/Mrp2) in rats2011

    • Author(s)
      Takayuki Noda
    • Journal Title

      J.Infect.Chemother.

      Volume: Vol.17 Pages: 207-213

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetic-pharmacodynamic study of itraconazole in patients with fungal infections in intensive care units2011

    • Author(s)
      Mao Hagihara
    • Journal Title

      J.Infect.Chemother.

      Volume: Vol.17 Pages: 224-230

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] β-Glucuronidase activity is a sensitive biomarker to assess low-level organophosphorus insecticide exposure.2010

    • Author(s)
      Ueyama J, Satoh T, Kondo T, Takagi K, Shibata E, Goto M, Kimata A, Saito I, Hasegawa T, Wakusawa S, Kamijima M
    • Journal Title

      Toxicol Lett. 133

      Pages: 115-119

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] a novel WD40-repeat protein, mediates spontaneous and tumor necrosis factor-induced apoptosis.2010

    • Author(s)
      Feng GG, Li C, Huang L, Tsunekawa K, Sato Y, Fujiwara Y, Komatsu T, Honda T, Fan JH, Goto H, Koide T, Hasegawa T, Ishikawa N, Naofen
    • Journal Title

      Biochem. Biophys. Res.Commun. 394

      Pages: 153-157

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Active ingredients of traditional Japanese (kampo) medicine, inchinkoto, in murine concanavalin A-induced hepatitis.2010

    • Author(s)
      Mase A, Makino B, Tsuchiya N, Yamamoto M, Kase Y, Takeda S, Hasegawa T
    • Journal Title

      J.Ethnopharmacol. 127

      Pages: 742-749

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Association between gefitinib and hemorrhagic cystitis and severely contracted bladder : a case report2010

    • Author(s)
      Maki Arakawa
    • Journal Title

      BMC

      Volume: VOL.10 Pages: 6-8

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Active ingredients of traditional Japanese (kampo) medicine, inchinkoto, in murine concanavalin A-induced hepatitis2010

    • Author(s)
      Akihito Mase
    • Journal Title

      J.Ethnopharmacol.

      Volume: VOL.127 Pages: 742-749

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats : possible correlation to apoptosis of tubular epithelial cells.2010

    • Author(s)
      Yuko Sato
    • Journal Title

      Clin.Exp.Nephrol.

      Volume: VOL.14 Pages: 205-212

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of 1-O-hexyl-2,3,5-trimethylhydroquinone on carbon tetrachloride-induced hepatic cirrhosis in rats2010

    • Author(s)
      Jun An
    • Journal Title

      Hepatol.Res.

      Volume: VOL.40 Pages: 566-573

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CYP2C19遺伝子解析結果からみたボリコナゾール血中濃度モニタリングの臨床的意義2010

    • Author(s)
      木村匡男
    • Journal Title

      Jpan.J.Antibiot.

      Volume: VOL.63 Pages: 255-264

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Naofen, a novel WD40-repeat protein, mediates spontaneous and tumor necrosis factor-induced apoptosis2010

    • Author(s)
      Feng Guo-Gang
    • Journal Title

      Biochem.Biophys.Res.Commun. 394

      Pages: 153-157

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of hepatic branched-chain α-keto acid dehydrogenase kinase in a rat model for type 2 diabetes mellitus at different stages of the disease2010

    • Author(s)
      Masao Doisaki
    • Journal Title

      Biochem.Biophys.Res.Commun. 393

      Pages: 303-307

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of a Kampo preparation, byakkokaninjinto, on pharmacokinetics of ciprofloxacin and tetracycline.2009

    • Author(s)
      Ohnishi M, Hitoshi K, Katoh M, Nadai M, Abe F, Kurono S, Haniuda M, Saito H, Hasegawa T
    • Journal Title

      Biol.Pharm.Bull. 32

      Pages: 1080-1084

    • NAID

      130000117191

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Urinary excretion of 3-phenoxybenzoic acid in middle-aged and elderly general population of Japan.2009

    • Author(s)
      Ueyama J, Kimata A, Kamijima M, Hamajima N, Ito Y, Suzuki K, Inoue T, Yamamoto K, Takagi K, Saito I, Miyamoto K.-I, Hasegawa T, Kondo T
    • Journal Title

      Environ.Res. 109

      Pages: 175-180

    • NAID

      120001008419

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Heme oxygenase-1 mediates the anti-allergic actions of quercetin in rodent mast cells.2009

    • Author(s)
      Matsushima, M., Takagi, K., Ogawa M., Hirose E., Ota Y., Abe F., Baba K., Hasegawa T., Hasegawa T, Kawabe T
    • Journal Title

      Inflamm.Res. 58

      Pages: 705-715

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effect of a Kampo preparation, byakkokaninjinto, on pharmacokineticsof ciprofloxacin and tetracycline2009

    • Author(s)
      Masafumi Ohnishi
    • Journal Title

      Biol.Pharm.Bull. 32

      Pages: 1080-1084

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Urinary excretion of 3-phenoxybenzoic acid in middle-aged and elderly general population of Japan2009

    • Author(s)
      Jun Ueyama
    • Journal Title

      Environ.Res. 109

      Pages: 175-180

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Possible involvement of interleukin-6(IL-6)in down-regulation of hepatic breast cancer resistance protein(Bcrp/ABCG2)in endotoxemic mice2009

    • Author(s)
      Zhao Ying Lan
    • Journal Title

      Bull.Aichi Bunkyo Women's College 30

      Pages: 27-42

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heme oxygenase-1 mediates the anti-allergic actions of quercetin in rodent mast cells2009

    • Author(s)
      Miyoko Matsushima
    • Journal Title

      Inflamm.Res. 58

      Pages: 705-715

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] β-Glucuronidase activity is a sensitive biomarker to assess low-level organophosphorus insecticide exposure2009

    • Author(s)
      Jun Ueyama
    • Journal Title

      Toxicol Lett. 133

      Pages: 115-119

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Possible involvement of initerleukin-6(IL-6)in down-regulation of hepatic breast cancer resistance protein (Bcrp/ABCG2)in endotoxemic mice2009

    • Author(s)
      Ying Lan Zhao
    • Journal Title

      Bull. Aichi Bunkyo Women's College 30

      Pages: 27-42

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of a kampo preparation, byakkokaninjinto, on Pharmacokinetics of ciprofloxacin and tetracycline2009

    • Author(s)
      Masafumi Ohnishi
    • Journal Title

      Biol. Pharm. Bull. 32(In press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of serum NOx level with clustering of metabolic syndrome components in middle-aged and elderly general populations in Japan.2008

    • Author(s)
      Ueyama J, Kondo T, Imai R, Kimata A, Yamamoto K, Suzuki K, Inoue T, Ito Y, Miyamoto K.-I, Hasegawa T, Hamajima N
    • Journal Title

      Environ. Health Preventive Med. 13

      Pages: 36-42

    • NAID

      210000099925

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effect of Thalidomide on Endotoxin-Induced Decreases in Activity and Expression of Hepatic Cytochrome P450 3A2.2008

    • Author(s)
      Ueyama J, Nadai M, Zhao YL, Kanazawa H, Takagi K, Kondo T, Takagi K, Wakusawa S, Abe F, Saito H, Miyamoto K, Hasegawa T
    • Journal Title

      Biol.Pharm.Bull. 31

      Pages: 1598-1600

    • NAID

      110006839024

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of multidrug resistance associated protein 2(ABCC2/Mrp2) in biliary excretion of micafungin in rats.2008

    • Author(s)
      Abe F, Ueyama J, Kimata A, Kato M, Hayashi T, Nadai M, Saito H, Takeyama N, Noguchi H, Hasegawa T
    • Journal Title

      Life Sci. 83

      Pages: 229-235

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Role of plasma proteins in pharmacokinetics of micafungin, an antifungal antibiotic, in analbuminemic rats.2008

    • Author(s)
      Abe F, Ueyama J, Kawasumi N, Nadai M, Hayashi T, Kato M, Ohnishi M, Saito H, Takeyama N, Hasegawa T
    • Journal Title

      Antimicrob. Agents Chemother. 52

      Pages: 3454-3456

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cyclooxygenase-2 expression in invasive transitional cell carcinoma of the urinary bladder.2008

    • Author(s)
      Yamada Y, Nakamura K, Inoue Y, Naruse K, Aoki S, Taki T, Tobiume M, Zennami K, Katsuda R, Hara K, Kyoku I, Mitsutake N, Arakawa M, Saito H, Hasegawa T, Noguchi H, Honda N
    • Journal Title

      Mol.Med.Reports 1

      Pages: 791-795

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effect of the organophosphoruspesticide diazinon on glucose tolerance in type 2 diabetic rats.2008

    • Author(s)
      Ueyama J, Kamijima M, Asai K, Mochizuki A, Wang D, Kondo T, Suzuki T, Takagi K, Takagi K, Kanazawa H, Miyamoto K, Wakusawa S, Hasegawa T
    • Journal Title

      Toxicol. Lett. 182

      Pages: 42-47

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Quality of life improvement in patients diagnosed with hormone refractory prostate cancer with bone metastatis as a result of chemotherapy and the administration of zoledronic acid.2008

    • Author(s)
      Arakawa M, Saito H, Hasegawa T, Kato Y, Ishikawa K
    • Journal Title

      Palliative Care Res. 3

      Pages: 308-315

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of pro-inflammatory mediators in endotoxin-induced overproduction of inducible nitric oxide synthase and decrease in expression of hepatic cytochrome P4502008

    • Author(s)
      Jun Ueyama
    • Journal Title

      Bull. Aichi Bunkyo Women's College 29

      Pages: 39-49

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A22008

    • Author(s)
      Jun Ueyama
    • Journal Title

      Biol. Pharm. Bull. 31

      Pages: 1598-1600

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of multidrug resistance-associated protein2 (ABCC2/Mrp2)in biliary excretion of micafungin in rats2008

    • Author(s)
      Fumie Abe
    • Journal Title

      Life Sci. 83

      Pages: 229-235

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of serum NOx level with clustering of metabolic syndrome components in middle-aged elderly general populations in Japan.2008

    • Author(s)
      Jun Ueyama
    • Journal Title

      Environ. Health Preventive Med. 13

      Pages: 36-42

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of plasma proteins in pharmacokinetics of micafung in, an antifungal antibiotic, in analbuminemic rats2008

    • Author(s)
      Fumie Abe
    • Journal Title

      Antimicrob. Agents Chemother. 52

      Pages: 3454-3456

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cyclooxygenenase-2 expression in invasive transitional cell carcinoma of the urinary bladder2008

    • Author(s)
      Yoshiyuki Yamada
    • Journal Title

      Mo1. Med. Reports 1

      Pages: 791-795

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of the organophosphoruspesticide diazinon on glucose tolerance in type 2 diabetic rats2008

    • Author(s)
      Jun Ueyama
    • Journal Title

      ToxicolLett. 182

      Pages: 42-47

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Quality of life improvement in patients diagnosed with Hormone refractory prostate cancer with bone metastatis as a result of chemotherapy and the administration of zoledronic acid2008

    • Author(s)
      Maki Arakawa
    • Journal Title

      Palliative Care Res 3

      Pages: 308-315

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetic-pharmacodynamic study of itraconazole in patientswith fungal infections in intensive care units.

    • Author(s)
      Hagihara M, Kasai H, Umemura T, Kato T, Hasegawa T, Mikamo H
    • Journal Title

      J.Infect. Chemother. 17

      Pages: 224-230

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Panipenem does not alter the pharmacokinetics of the active metabolite of irinotecan SN-38 and SN-38 glucuronide (SN-38G) in rats.

    • Author(s)
      Kato A, Ueyama J, Abe F, Hotta K, Tukiyama I, Ohshima T, Saito H, Hasegawa T
    • Journal Title

      Anticancer Res. in press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats : possible correlation to apoptosis of tubular epithelial cells

    • Author(s)
      Yuko Sato
    • Journal Title

      Clin.Exp.Nephrol. (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Revised method for routine determination of urinary dialkyl phosphates using gas chromatography-mass spectrometry

    • Author(s)
      Jun Ueyama
    • Journal Title

      J.Chromatogr.B (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Book] 臨床への薬物動態学2011

    • Author(s)
      長谷川高明
    • Total Pages
      299
    • Publisher
      廣川書店
    • Related Report
      2010 Annual Research Report
  • [Book] 臨床への薬物動態学2009

    • Author(s)
      岩川精吾, 他
    • Total Pages
      311
    • Publisher
      廣川書店
    • Related Report
      2010 Final Research Report
  • [Book] 臨床への薬物動態学2009

    • Author(s)
      長谷川高明
    • Total Pages
      311
    • Publisher
      廣川書店
    • Related Report
      2009 Annual Research Report
  • [Book] 臨床への薬物動態学2009

    • Author(s)
      岩川精吾
    • Total Pages
      311
    • Publisher
      廣川書店
    • Related Report
      2008 Annual Research Report
  • [Book] シンプル薬理学2008

    • Author(s)
      石川直久, 他
    • Total Pages
      328
    • Publisher
      南江堂
    • Related Report
      2010 Final Research Report
  • [Book] シンプル薬理学2008

    • Author(s)
      石川直久
    • Total Pages
      328
    • Publisher
      南江堂
    • Related Report
      2008 Annual Research Report
  • [Remarks]

    • URL

      http://www.aichi-med-u.ac.jp/

    • Related Report
      2010 Annual Research Report

URL: 

Published: 2008-04-01   Modified: 2016-04-21  

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