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The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis : The contribution of dimethylarsenic radicals and dimethylarsenic peroxide

Research Project

Project/Area Number 14572114
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Environmental pharmacy
Research InstitutionNihon University

Principal Investigator

YAMANAKA Kenzo  Nihon University, College of Pharmacy, Associate Prof., 薬学部, 助教授 (50182572)

Co-Investigator(Kenkyū-buntansha) KATO Koichi  Nihon University, College of Pharmacy, Assistant Prof., 薬学部, 講師 (60246931)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Keywordsdimethylarsinic acid / trivalent dimethylated arsenic / dimethylarsenic peroxy radical / oxidative stress / arsenic carcinogenesis / inorganic arsenics / metabolic mathylation / 小核形成 / ジメチルアルシン / 8-oxodG / チミングリコール / ジメチルヒ素 / 8-OHdG / 発がんプロモーション
Research Abstract

In recent research of arsenic carcinogenesis, many researchers have directed their attention to methylated metabolites of inorganic arsenics. Because of its high cytotoxicity and genotoxicity, trivalent dimethylated arsenic, which can be produced by the metabolic reduction of dimethylarsinic acid(DMA), has attracted considerable attention from the standpoint of arsenic carcinogenesis. We examined trivalent dimethylated arsenic and its further metabolites for their chemical properties and biological behavior such as genotoxicity and tumorigenicity. Our in vitro experiments suggested that the formation of cis-thymine glycol in DNA was induced via the production of dimethylated arsenic peroxide by the reaction of trivalent dimethylated arsenic with molecular oxygen, but not via the production of common reactive oxygen species (ROS ; superoxide, hydrogen peroxide, hydroxyl radical, etc.). Two-step tumorigenesis test in mice suggested that oxidative stress by exposure to trivalent dimethylated arsenic plays an important role in tumor promotion in skin. Thus, dimethylated arsenic peroxide may be the main species responsible for the tumor promotion in skin tumorigenesis induced by exposure to DMA. Micronucleus assay using peripheral blood reticulocytes of mice suggested that dimethylarsine, which is probably a further reductive metabolite of trivalent dimethylated arsenic, is primarily responsible for DNA damage rather than trivalent dimethylated arsenic. Free radical species, such as dimethylarsenic radical [(CH_3)_2As・] and/or dimethylarsenic peroxy radical [(CH_3)_2AsOO・], that are produced by the reaction of molecular oxygen and dimethylarsine [(CH_3)_2AsH], may be main agents for initiation in mouse-lung tumorigenesis.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (17 results)

All 2005 2004 2003 Other

All Journal Article (15 results) Publications (2 results)

  • [Journal Article] Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice.2005

    • Author(s)
      Y.An, K.Kato, M.Nakano, H.Otsu, S.Okada, K.Yamanaka
    • Journal Title

      Cancer Letters (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The Role of trivalent dimethylated arsenic in dimethylarsinic acid-promoted skin and lung tumorigenesis in mice : Tumor promoting action through the induction of oxidative stress2005

    • Author(s)
      M.Mizoi, F.Takabayashi, M.Nakano, Y.An, Y.Sagesaka, K.Kato, S.Okada, K.Yamanaka
    • Journal Title

      Toxicology Letters (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice.2005

    • Author(s)
      Y.An, K.Kato, M.Nakano, H.Otsu, S.Okada, K.Yamanaka
    • Journal Title

      Cancer Letters (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The Role of trivalent dimethylated arsenic in dimethylarsinic acid-promoted skin and lung tumorigenesis in mice : Tumor promoting action through the induction of oxidative stress.2005

    • Author(s)
      M.Mizoi, F.Takabayashi, M.Nakano, Y.An, Y.Sagesaka, K.Kato, S.Okada, K.Yamanaka
    • Journal Title

      Toxicology Letters (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice2005

    • Author(s)
      Yan An et al.
    • Journal Title

      Cancer Letters (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The role of trivalent dimethylated arsenic in dimethylarsinic acid-promoted skin and lungtumorigenesis in mice : Tumor promoting action through the induction of oxidative stress2005

    • Author(s)
      Mutsumi Mizoi et al.
    • Journal Title

      Toxicology Letters (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.2004

    • Author(s)
      K.Yamanaka, K.Kato, M.Mizoi, Y.An, F.Takabayashi, M.Nakano, M.Hoshino, S.Okada
    • Journal Title

      Toxicology and Applied Pharmacology 198

      Pages: 385-393

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China.2004

    • Author(s)
      Y.An, Z.Gao, Z.Wang, S Yang, J.Liang, Y.Feng, K.Kato, M.Nakano, S.Okada, K.Yamanaka
    • Journal Title

      Cancer Letters 214

      Pages: 11-18

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.2004

    • Author(s)
      K.Yamanaka, K.Kato, M.Mizoi, Y.An, F.Takabayashi, M.Nakano, M.Hoshino, S.Okada
    • Journal Title

      Toxicology and Applied Pharmacology 198(3)

      Pages: 385-393

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China.2004

    • Author(s)
      Y.An, Z.Gao, Z.Wang, S.Yang, J.Liang, Y.Feng, K.Kato, M.Nakano, S.Okada, K.Yamanaka
    • Journal Title

      Cancer Letters 214(1)

      Pages: 11-18

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China2004

    • Author(s)
      Yan An et al.
    • Journal Title

      Cancer Letters 214

      Pages: 11-18

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis2004

    • Author(s)
      Kenzo Yamanaka et al.
    • Journal Title

      Toxicology and Applied Pharmacology 198

      Pages: 385-393

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Oxidative DNA damage following exposure to dimethylarsinous iodide : The formation of cis-thymine glycol.2003

    • Author(s)
      K.Yamanaka, M.Mizoi, M.Tachikawa, A Hasegawa, M.Hoshino, S.Okada
    • Journal Title

      Toxicology Letters 143

      Pages: 145-153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Active arsenic species produced by GSH-dependent reduction of dimethylarsinic acid cause micronuclei formation in peripheral reticulocytes of mice.2003

    • Author(s)
      Koichi Kato, K.Yamanaka, A.Hasegawa, S.Okada
    • Journal Title

      Mutation Research 539

      Pages: 55-63

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Oxidative DNA damage following exposure to dimethylarsinous iodide : The formation of cis-thymine glycol.2003

    • Author(s)
      K.Yamanaka, M.Mizoi, M.Tachikawa, A.Hasegawa, M.Hoshino, S.Okada
    • Journal Title

      Toxicology Letters 143

      Pages: 145-153

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Koichi Kato et al.: "Active arsenic species produced by GSH-dependent reduction of dimethylarsinic acid cause micronuclei formation in peripheral reticulocytes of mice."Mutation Research. 539. 55-63 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kenzo Yamanaka 他5名: "Oxidative DNA Damage Following Exposure to Dimethylarsinous Iodid: The Formation of Cis-Thymine Glycol"Toxicology Letters. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report

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

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