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Novel metabolic pathway for activation of carcinogenic N-nitroso compounds by reactive oxygen species

Research Project

Project/Area Number 15590113
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Environmental pharmacy
Research InstitutionKyoritsu University of Pharmacy

Principal Investigator

MOCHIZUKI Masataka  Kyoritsu University of Pharmacy, Professor, 薬学部, 教授 (10072414)

Co-Investigator(Kenkyū-buntansha) ISHIKAWA Satoko  Kyoritsu University of Pharmacy, Research Associate, 薬学部, 助手 (70223518)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsN-nitrosodialkylamines / Fenton reagent / reactive oxygen species / mutagenicity / metabolic activation / ヒドロキシラジカル / 突然変異原生 / DNA損傷
Research Abstract

N-Nitrosodialkylamines are metabolized by cytochrome P450, and formed alkyldiazonium ions through α-hydroxylnitrosamines, and then finally showed mutagenicity and carcinogenicity. However, the precise process of their activation is less well understood. N-Nitrosodialkylamines were treated with hydroxyl radical generating system, ferrous ion-cupric ion-hydrogen peroxide system (defined as modified Fenton reagent), and mutagens formed in this system were identified in order to investigate a novel metabolic pathway of N-nitroso compounds.
N-Nitroso-N-methylbutylamine (NMB) showed mutagenicity after treatment with modified Fenton reagent. We already reported that 5-methyl-5-nitro-1-pyrazoline 1-oxide (mutagenX) as a novel mutagen identified from the reaction mixture of NMB and modified Fenton reagent. Mutagen X was synthesized and tested the mutagenicity. Furthermore, mutagen X in the reaction mixture was quantified, and then compared the mutagenicities among the reaction mixture and mutagen X alone. The mutagenicity of reaction mixture was higher than that of mutagen X alone by a factor of 15. The result showed that there are possibilities of other stronger mutagen formed or of enhancement of the mutagenicity by other products in the reaction mixture. In this study, we isolated another mutagen, showed higher mutagenicity than mutagen X, from the reaction mixture of NMB and modified Fenton reagent.
Further research is necessary to identify the novel metabolite and elucidate the mechanism of its formation in the reaction mixture of N-nitroso compounds treated with reactive oxygen species.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (10 results)

All 2005 2004 2003 Other

All Journal Article (9 results) Publications (1 results)

  • [Journal Article] Electron-transfer mechanism in radical-scavenging reactions by a vitamin E model in a protic medium.2005

    • Author(s)
      Nakanishi I, Kawashima T, Ohkubo K, Kanazawa H, Inami K, Mochizuki M, Fukuhara K, Okuda H, Ozawa T, Itoh S, Fukuzumi S, Ikota N.
    • Journal Title

      Org Biomol Chem 3

      Pages: 626-629

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synthesis and properties of bifunctional chloroalkyl-nitrosamines with an intercalating moiety.2004

    • Author(s)
      Ishikawa S, Tajima M, Mochizuki M.
    • Journal Title

      Bioorg Med Chem 12

      Pages: 3791-3796

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synthesis and properties of bifunctional chloroalkyl nitrosamines with an intercalating moiety.2004

    • Author(s)
      Ishikawa S, Tajima M, Mochizuki M.
    • Journal Title

      Bioorg Med Chem 12

      Pages: 3791-3796

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sunthesis and properties of bifunctional chloroalkyl nitrosamines with an intercalating moiety.2004

    • Author(s)
      Ishikawa S, Tajima M, Mochizuki M.
    • Journal Title

      Bioorganic & Medicinal Chemistry 12

      Pages: 3791-3796

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prevention of PU.1-induced growth inhibition and apoptosis but not differentiation block in murine erythroleukemia cells by overexpression of CBP.2003

    • Author(s)
      Manabe N, Yamamoto H, Yamada T, Kihara-Negishi F, Hashimoto Y, Mochizuki M, Oikawa T.
    • Journal Title

      Int J Oncol 22

      Pages: 1345-1350

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A practical approach for the chemical synthesis of 2'-deoxyguanosine-C8 adducts with mutagenic/carcinogenic amino- or nitro-arenes.2003

    • Author(s)
      Takamura-Enya T, Ishikawa S, Mochizuki M, Wakabayashi K.
    • Journal Title

      Tetrahedron Lett 44

      Pages: 5969-5973

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutagenicity and cross-linking activity of chloroalkylnitros amines, possible new antitumor lead compounds.2003

    • Author(s)
      Ishikawa S, Mochizuki M.
    • Journal Title

      Mutagenesis 18

      Pages: 331-335

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Kinetic study of the electron-transfer oxidation of the phenolate anion of a vitamin E model by molecular oxygen generating superoxide anion in an aprotic medium.2003

    • Author(s)
      Nakanishi I, Miyazaki K, Shimada T, Iizuka Y, Inami K, Mochizuki M, Urano S, Okuda H, Ozawa T, Fukuzumi S, Ikota N, Fukuhara K.
    • Journal Title

      Org Biomol Chem 1

      Pages: 4085-4088

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutagenicity and cross-linking activity of chloroalkylnitrosamines, possible new antitumor lead compounds.2003

    • Author(s)
      Ishikawa S, Mochizuki M.
    • Journal Title

      Mutagenesis 18

      Pages: 331-335

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Ishikawa S, Mochizuki M.: "Mutagenicity and cross-linking activity of chioroalkylnitrosamines, possible new antitumor lead compounds"Mutagenesis. 18(4). 331-335 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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