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2000 Fiscal Year Final Research Report Summary

Functional characterization and relevance of carnitine transporter OCTN2 to secondary carnitine deficiency.

Research Project

Project/Area Number 11672212
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionKANAZAWA UNIVERSITY

Principal Investigator

TAMAI Ikumi  Kanazawa University, Graduate School, Associate Professor, 大学院・自然科学研究科, 助教授 (20155237)

Co-Investigator(Kenkyū-buntansha) TSUJI Akira  Kanazawa University, Pharmacy, Professor, 薬学部, 教授 (10019664)
Project Period (FY) 1999 – 2000
Keywordscarnitine / transporter / organic cations / carnitine deficiency / OCTN / drugs / renal reabsorption / avtive secretion
Research Abstract

In the present study, novel Na^+-dependent carnitine/organic cation transporter family, OCTNs from human and mouse were identified and functionally characterized. We isolated two and three members of OCTN family from human and mouse, respectively. OCTNs are present in various tissues, including kidney, heart, skeletal muscle and placenta strongly, and in several human-derived cancer cell lines. By immunohistochemical analysis in kidney, mouse OCTNs localized commonly in luminal membrane of tubular epithelial cells. Most of human and mouse OCTNs exhibited multifunctionality by transporting both of carnitine and organic cation, tetraethylammonium (TEA). Furthermore, sodium ions were essential for carnitine transport by human and mouse OCTN1 and 2. In systemic carnitine deficiency (SCD) phenotype mouse model, juvenile visceral steotosis (jvs) mouse, mutation in OCTN2 gene was found. Furthermore, several kinds of mutation in human SCD patients were found, demonstrating that OCTN2 is a physiologically important carnitine transporter. Interestingly, TEA transport was sodium independent. In addition, OCTNs transporterd various cationic drugs such as quinidine, verapamil, and actinomycin D.Furthermore, since one mutation of human OCTN2 lost carnitine transport activity but retained TEA transport activity, it was suggested that OCTN2 have differential functional sites for carnitine and organic cations. So, OCTNs are thought to be multifunctional transporters by transporting carnitine and organic cations by sodium ion dependent and independent manner, respectively, and would be important for disposition of organic cationic drugs as well as carnitine. Furthermore, since carnitine transport via OCTN2 is inhibited various compounds, including organic cations, organic anions such as valproic acid and neutral compound such as cortisole, it is anticipated that drug-induced secondary carnitine deficiency could be caused by interaction on OCTN2.

  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Yokogawa K.: "Decreased tissue distribution of L-carnitine injunenile misceral steatitis mice."J.Pharmacol.Exp.Ther.. 289. 224-230 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yabuuchi,H.: "Novel membrane transporter OCTN1 mediates multispecific,indirectional and pH-dependent transport of organic cations."J.Pharmacol.Exp.Ther.. 289. 768-773 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yokogawa,K.: "Characteristics of L-carnitine transport in cultured hepatoma HL cells from man."J.Pharm.Pharmacol.. 51. 935-940 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yokogawa,K.: "Loss of wild-type carrier-mediated L-carnitine transport activity in hepatocytes of junenile steatos mice."J.Pharmacol.Exp.Ther.. 291. 778-784 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koizumi,A.: "Genetic epidemiology on carnitine transporter OCTN2 gene in Japanese population and phenotype characteristics in Japanese pedgrees with primary system carnitine deficient"Hum.Md.Genet.. 8. 2247-2254 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mayatepek,E.: "Two novel missense mutations of the OCTN2 gene(W283R and V446F)in a patient with primary systemio carnitine dificiency."Hum.Mutat.(on line). 15. 118 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tamai,I.: "Molecular and functional characterization of organic cation/carnitine transporter family in mice."J.Bial.Chem.. 275. 40064-40072 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yokogawa, K.: "Decreased tissue distribution of L-carnitine in juvenile visceral steatosis mice"J.Pharmacol.Exp.Ther.. 289 (1). 224-230 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yabuuchi, H.: "Novel membrane transporter OCTN1 mediates multispecific, bidirectional and pH-dependent transport of organic cations."J.Pharmacol.Exp.Ther.. 289 (2). 768-773 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yokogawa, K.: "Chatacteristics of L-carnitine transport in cultured hepatoma HLF cells from man."J.Pharm.Pharmacol.. 51 (8). 935-940 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yokogawa, K.: "Loss of wild-type carrier-mediated L-carnitine transport activity in hepatocytes of juvenile visceral steatosis mice."Hepatology. 30 (4). 997-1001 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohashi, R.: "Na^+-dependent carnitine transport by OCTN2 and its pharmacological and toxicological relevance."J.Pharmacol.Exp.Ther.. 291 (2). 778-784 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koizumi, A.: "Genetic epidemiology on carnitine transporter OCTN2 gene in a Japanese population and phenotype characterizations in Japanese pedigrees with primary systemic carnitine deficiency."Hum.Mol.Genet.. 8 (12). 2247-2254 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mayatepek, E.: "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency."Hum.Mutat. (Online). 15 (1). 118 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamai, I.: "Molecular and functional characterization of organic cation/carnitine transporter family in mice."J.Biol.Chem.. 275 (51). 40064-40072 (2000)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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