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Detoxification of tetrodotoxin by thiol sinthe liver of puffer fish

Research Project

Project/Area Number 14560080
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioproduction chemistry/Bioorganic chemistry
Research InstitutionTOHOKU University

Principal Investigator

YAMASHITA Mari  Tohoku University, Graduate School of Agricultural Science, Associate Professor, 大学院・農学研究科, 助教授 (50192430)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordspuffer fish / tetrodotoxin / defoxification / metabolism
Research Abstract

Metabolic pathway of tetrodotoxin (TTX, 1), a potent neurotoxin in puffer fish, has not been clarified yet, for puffer fish and also for human. We found a new natural analog of TTX, 4-L-cycteineTTX (4-CysTTX,2) from the liver of the puffer fish, Fugu pardalis, collected in spring in 2000. In this report, structural confirmation of 2, and the reaction of TTXs with thiols are described.
2 (ca. 0.4 mg) was isolated from 200 g of liver of the puffer fish by sequential liquid chromatography. Based on the spectroscopic data, 2 was determined as an analog of 1 of which equatorial hydroxyl group at C4 was substituted by sulfur atom of cysteine. Configuration of cysteine was confirmed to be L by using Marfey reagent for cysteine obtained from 2 by I_2 oxidation.
2 was produced by the reaction of 4,9-anhydroTTX (4) and large excess (100-500 equiv.) of cysteine in phosphate buffer (pH 7.0-8.0) at 40℃ for 90 mm. It was pH dependent reaction. Other thiols, glutathione (GSH), mercaptoethanol (ME), and cysteinyl glycine were similarly reacted with 4 to produce sulfur substituted compounds at C4 of 1. On the condition with much more excess of thiols (more than 20000 equiv.) and for longer reaction time (longer than 8 hr), ME and GSH were also reacted with 1 to produce the same derivatives from 4.
We also confirmed that 4-glutathioneTTX was hydrolyzed by glutamyltranspeptidase to 4-cysteinylglysineTTX, and then to 2 by the dipeptidase. According to the results of mouse bioassay, oral administration of thiols. with TTX was not effective to decrease the toxicity of TTX, contrary to the results by Fujii et al.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Mari Yotsu-Yamashita, et al.: "The structure of zetekitoxin AB, a novel saxitoxin analog from the golden frog Atelopus zeteki : a potent sodium channel blocker"Proc.Natl.Acad.Sci.USA. 101-13. 4346-4351 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yong Hae Kim, Mari Yotsu-Yamashita: "Potent neurotoxins : Tetrodotoxin, chiriquitoxin, and zetekitoxin from Atelopus frogs of Central America"J.Toxicol.Toxin Reviews. 22-4. 521-532 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita, Dietrich Mebs: "Occurrence of 11-oxotetrodotoxin in the red-spotted newt, Notophthalmus viridescens, and further studies on the levels of tetrodotoxin"Toxicon. 41. 893-897 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita, et al.: "Biological activity of 8,11-dideoxytetrodotoxin : Lethality to mice and the inhibitory activity to cytotoxicity of ouabain and veratridine"Toxicon. 42. 557-560 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 山下 まり: "動物成分としての毒"朝倉書店. 5 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita: "The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki : a potent sodium-channel blocker"Proc.Natl.Acad.Sci.USA. 101(13). 4346-4351 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yong Hae Kim: "Tetrodotoxin, chiriquitoxin, and zetekitoxin from Atelopus frogs of Central America"J.Toxicol.Toxin Reviews. 22(4). 521-532 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita: "Biological activity of 8,11-dideoxytetrodotoxin : lethality to mice and the inhibitory activity to cytotoxicity of ouabain and veratridine in mouse neuroblastoma cells"Toxicon. 42. 557-560 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita: "11-oxotetrodotoxin in the red-spotted newt, Notophthalmus viridescens, and further studies on the levels of tetrodotoxin and its analogues in the newt's efts"Toxidon. 41. 893-897 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita: "Animal Toxins"Animal Toxins, Dictionary of Agricultural chemistry (in Japanese)(Asakura-shoten). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mari Yotsu-Yamashita et al.: "The structure of zetekitoxin AB, a novel saxitoxin analog from the golden frog Atelopus zeteki : a potent and selective sodium channel blocker"Proc.Natl.Acad.Sci.USA. 101(13). 4346-4351 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yong Hae Kim, Mari Yotsu-Yamashita: "Potent neurotoxins : Tetrodotoxin, chiriquitoxin, and zetekitoxin from Atelopus frogs of Central America"J.Toxicol.Toxin Reviews. 22(4). 521-532 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mari Yotsu-Yamashita, Dietrich Mebs: "Occurrence of 11-oxotetrodotoxin in the red-spotted newt, Notophthalmus viridescens, and further studies on the levels of tetrodotoxin and its analogues in the newt efts"Toxicon. 41. 893-897 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Marl Yotsu-Yamashita et al.: "Biological activity of 8,11-dideoxytetrodotoxin : Lethality to mice and the inhibitory activity to cytotoxicity of ouabain and veratnidine in mouse neuroblastoma cells, Neuro-2a"Toxicon. 41. 557-560 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 山下まり: "動物成分としての毒"朝倉書店. 5 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Maii Yotsu-Yamashita, et al.: "Mutual inhibition of tetrodotoxin and saxitoxin binding to their binding protein from plasma of the puffer fish, Fugu pardalis"Biosci.Biotechnol.Biochem.. 66. 2520-2524 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Gaurav Choudhary, et al.: "Interactions of C-11 Hydroxyl of Tetrodotoxin with the Sodium Channel Outer Vestibule"Biophys.J.. 84. 287-294 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mari Yotsu-Yamashita: "Sodium Channels of Puffer Fish"Nippon Suisan Gakkaishi. 68. 925-926 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tagiri-Endo, M, et al.: "Ozonation of phosphatidylcholine in ethanol : separation and identification of a novel ethoxyhydroperoxide"Lipids. 37. 1007-1012 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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