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Molecular cloning and functional expression of kidney-specific organic anionic drug transporters

Research Project

Project/Area Number 09470025
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKyorin University School of Medicine

Principal Investigator

ENDOU Hitoshi  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Professor, 医学部, 教授 (20101115)

Co-Investigator(Kenkyū-buntansha) SEKINE Takashi  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (50255402)
TAKEDA Michio  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Lecturer, 医学部, 講師 (40255401)
KANAI Yoshikatsu  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Lecturer, 医学部, 助教授 (60204533)
CHA Seok ho  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (50276200)
HOSOYAMADA Makoto  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (00291659)
INATOMI Jun  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant (00311960)
楯 直子  杏林大学, 医学部, 助手 (00201955)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1997: ¥4,400,000 (Direct Cost: ¥4,400,000)
Keywordsorganic anion / organic anion transporter / para-amino hippurate / estron sulfate / ochratoxin A / organic cation transporter / carnitine transporter / multispecific substrate recognition / 近位尿細管中間部 / ジカルボン酸 / トランスポーター / ジカルボン酸トランスポーター / 薬物輸送
Research Abstract

Most drugs ingested into the body are metabolized by drug-metabolizing enzymes in the liver, and converted to more polarized hydrophilic compounds. Thus formed drug metabolites contain either negative or positive charge, and more anionic compounds are produced. To eliminate these drug metabolites out of the body, specific membrane proteins named transporters are required.
There are two major pathways for drug elimination, one of which is hepatic one through bile and another is renal one to urine. In this investigation, we tried to clone kidney-specific organic anion transporters, and to characterize several isoforms.
In 1997, we could succeed to isolate a novel organic anion transporter from rat kidneys and named it OAT (organic anion transporter) 1. Thereafter, three members of OAT family have been identified. OAT2 is liver-specific having different spectrum of transport substrates from OAT1. OAT3 having 536 amino acid residue is expressed in the liver, kidney and brain showing 49% and 39% identities with OAT1 and OAT2, respectively. OAT3 mediates high affinity transport of PAH, ochratoxin A, and estron sulfate. Human OAT4 is expressed in the kidney and placenta and consists of 550 amino acids having identity at 38%〜44% with OAT1〜3. The OAT4 is also multispecific in substrate recognition, like estron sulfate, dehydroepiandrosterone sulfate, and ochratoxin A.
Although we could chine 4 isoforms of OAT family, OAT1〜4, molecular mechanisms on substrate recognition remain to be carried out by further investigation. Since OATs reveal weak but significant similarity in their structure with organic cation transporters and carnitine transporters, possible molecular evolution should be clarified among these families. The multi specificity seen in OATs may be originated from relatively simple substrate binding to the transporters and the hypothesis of two important biding sites like hydrophobic moiety and ionic charge needs to be elucidated.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Hosoyamada,M.: "Molecular cloning and functionalexpression of a multispecific organic anion transporter from human kidney"Am.J.Physiol.. 276(459). F122-F128 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tojo,A.: "Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney."10. 464-471 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kusuhara,H.: "Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain."J.Biol.Chem.. 274(19). 13675-13680 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Apiwattanakul,N.: "Transport properities of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes."Mol.Pharmacol.. 55. 847-854 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Piyachaturawat,P.: "Effect of chronic K^+ deficiency on contractile properties of soleus muscle in rats:Evidence of sex differences."Clin.Exp.Pharmacol.Physiol.. 26. 323-329 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsuda,M.: "Transport of ochratoxin A by renal multispecific organic anion transporter 1."J.Pharmacol.Exp.Ther.. 289(33). 1301-1305 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Cha,S.H.: "Silica increases cytosolic calcium and causes cell injury in renal cell lines."Industrial Health. 37. 330-306 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Segawa,H.: "Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity."J.Biol.Chem.. 274(28). 19745-19751 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Jariyawat,S.: "The interaction and transport of β-lactam antibiotics with the cloned rat organic anion tranporter 1"J.Pharmacol.Exp.Ther.. 290(2). 672-677 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Oku,A.: "T-1095,and Inhibitor of renal Na^+-glucose cotransporters,may provide a novel approach to treating diabetes."Diabetes. 48. 1794-1800 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Arthit,C.: "Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein."J.Biol.Chem.. 274(41). 28845-28848 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Igarashi,T.: "Mutations in SLC4A4 cause permanent isolated proximal renal tubular cidosis with ocular abnormalities."Nature Genetics. 23. 264-266 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takeda,M.: "Role of organic anion transporter 1(OAT1)in cephaloridine(CER)-induced nephrotoxicity."Kidney Int.. 56. 2128-2136 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Cha,S.H.: "Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta."J.Bioll Chem.. 275. 4507-4512 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okuda,I.: "Identification and characterization of high-affinity choline transporter."Nature Neuroscience. 3(2). 120-125 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 長沢俊彦: "Annual Review腎臓 2000"中外医学社. 255 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 植松俊彦: "シンプル 薬理学"南江堂. 278 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mori,M.: "Guanidino Compounds.5"Blackwell Science Asia Pty Ltd.. 480 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Cha,S.H.,Sekine,T.& of subtypes P2Y1 and P2Y2: "P2 purinoceptor localization along rat nephron and evidence suggesting existence Endou,H." Am.J.Physiol.274(43). F1006-F1014 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sekine,T.,Cha,S.H.,Tsuda,M.,Apiwattanakul,N.,Nakajima,N.,Kanai,Y.& Endou,H.: "Identification of multispecific organic anion transporter 2 expressed predominantly in the liver." FEBS Lett.429. 179-182 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sekine,T.,Cha,S.H.,Hosoyamda,M.,Kanai,Y.,Watanabe,N.,Furuta,Y.Fukuda K.,Igarashi,T.& Endou,H.: "Clloning,functional characterization,and localization of rat renal Na+-dicarboxylate transporter." Am.J.Physiol.275(44). F298-F305 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kanai,Y.,Segawa,H.,Miyamoto,K.,Uchino,H.,Takeda,E.& Endou,H.: "Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen(CD98)." J.Biol Chem. 273. 23629-23632 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hosoyamada,M.,Sekine,T.,Kanai,Y.& Endou,H.: "Molecular cloning,functionalexpression of a multispecific organic anion transporter from human kidney." Am.J.Physiol.276(459). F122-F128 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sekine,T.,Kusuhara,H.,Utsunomiya-Tate,N.,Tsuda,M.,Sugiyama,Y.,Kanai.,Y.& Endou,H.: "Molecular cloning and characterization of high-affinity carnitine transporter from ratintestine." Biochem.Biophys.Res.Comm.52(6). 251(2). 586-591 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 長沢俊彦、河邉香月、伊藤克己、浅野 泰、遠藤 仁: "Annual Review腎臓 1999" 中外医学社, 94 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 小椋秀亮、加藤有三、篠田 壽: "現代歯科薬理学第3版" 医歯薬出版株式会社, 314 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kim,H.S., Cha,S.K., Abraham,D.G., Cooper,A.J.L & Endou,H.: "Intranephron distribution of cysteine S-conjugate β-lyase activity and its implication for hexachloro-1,3-butadiene-induced nephrotoxicity in rats." Arch.Toxicol.71. 131-141 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nosaka,K., Takahashi,T., Nishi,T., Imaki,H., Suzuki,T., Suzuki,K., Kurokawa,K & Endou,H.: "An adenosine deaminase inhibitor prevents puromycin aminonucleoside Nephrotoxicity." Free Radical Biol.Med.22(4). 597-605 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeda,M.,Kobayashi,M., Osaki,T.,Shirato,I.& Endou,H.: "Staurosporine-induced apoptosis of immortalized mouse proximal tubule cells is modulated by BCL-2 expression level." Biochem.Mol.Biol.Int.42(4). 649-656 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sekine,T., Wananabe,N., Hosoyamada,M., Kanai,Y.& Endou,H.: "Expression cloning and characterization of a novel multispecific organic amion transporter." J.Biol.Chem.272(30). 18526-18529 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeda,M., Kobayashi,M., Shirato,I.,Osaki,T.& Endou,H.: "Cisplatin-induced apoptosis of immortalized mouse proximal tubule cells is mediated by interleukin-1β converting enzyme(ICE) family of proteases but inhibited by overexpression of Bcl-2." Arch.Toxicol.71. 612-621 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Utsunomiya-Tate,N., Endou,H.,& Kanai,Y.: "Tissue specific variants of glutamate transporter GLT-1." FEBS Let.416. 312-316 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Endou,H., Kanai,Y., Utsunomiya-Tate,N.& Hosoyamada,M.: "Contrib.Nephrol."Nutritional and acid-base aspects of amino acid metabolism"" Karger, 172 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 長沢俊彦、河邉香月、伊藤克己,浅野 泰、遠藤 仁: "Annual Review 腎臓 1998" 中外医学社, 239 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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