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2001 Fiscal Year Final Research Report Summary

The study on non-cholinergic toxicity of Nerve agents

Research Project

Project/Area Number 11670408
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Legal medicine
Research InstitutionNagoya City University

Principal Investigator

NAGAO Nasataka  Nagoya City University Medical School, Professor, 医学部, 教授 (80227991)

Co-Investigator(Kenkyū-buntansha) KOYAMA Hiroyoshi  Nagoya City University Medical School, Research Associate, 医学部, 助手 (10170408)
MAENO Yoshitata  Nagoya City University Medical School, Assistant Professor, 医学部, 講師 (00145749)
IWASA Mineo  Nagoya City University Medical School, Associate Professor, 医学部, 助教授 (00021452)
Project Period (FY) 1999 – 2001
KeywordsSarin / Soman / organophosphorous agent / rat / brain / PLCγ / MAPK / JNK / paraoxonase
Research Abstract

We report that there is a time-related change in the phospholipase C (PLC) activities of rat brain cytosol and membrane fractions after iv injection of a soman-like or a sarin-like organophosphorous agent (BIMP, bis (isopropyl methyl) phosphonate ; and BPMP, bis (pinacolyl methyl) phosphonate). PLCγ was activated in the brain cytosol fraction from BPMP- injected rats. The phosphorylating activity of rat brain membrane fractions were enhanced by BPMP treatment. The brain membrane fractions from BPMP-treated rats phosphorylated several proteins, including supposedly PLCγ in the brain cytosol fraction from control rats in vitro. These results suggest that soman and sarin may stimulate a membrane tyrosine kinase, including growth factor receptors, directly or indirectly.
BIMP and BPMP were injected intravenously (iv) in rats. An increase in the tyrosine phosphorylation of several proteins in the cytosol fraction of the brain was observed. Activation of c-Jun N-terminal kinase (JNK) and slight activation of mitogen activated protein kinase (MAPK) in the cytosol were also observed. The activation of these enzymes may be related to the high toxicity of these nerve agents.
We reported the polymorphism of the high density lipoprotein-associated enzyme paraoxonase (PON1), in the 10 sarin poisoning victims in the Tokyo subway terrorist attack. Arg_192 PON1, which has tow sarin hydrolysing activity, was found to be more common in the Japanese population than in people of other races. However, from our analyses seven of the victims expressed the phenotype with high sarin hydrolysing activity and three with low sarin hydrolysing activity. These results indicate that the main factor contributing to the tragedy of the Tokyo subway terrorist attack was high toxicity of sarin rather than the race-dependent genetic difference in the Arg_l92 PON1 polymorphism.

  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Niijima H, et al.: "Sarin-like and soman-like organophosphoeous angents activate PLCγ in rat brains"Toxical Appl Pharmacol. 156. 64-69 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Niijima H, et al.: "The effect of sarin-like and soman-like organophosphorous agents on MAPK and JNK in rat brains"Forensic Sci Int. 112. 171-178 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada Y, et al.: "Expression of paraoxonase isform did not confer protection from acute sarin poisoning in Tokyo subway Terrorist attack"Int J Legal Med. 115. 82-84 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Niijima H., Nagao M., Nakajima M. Takatori T., Matsuda Y., et al.: "Sarin-like and soman-like organophosphorous agents activate PLCγ in rat brains"Toxicol Appl Pharmacol. 156(1). 64-69 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Niijima H., Nagao M., Nakajima M., Takatori T. et al.: "The effects of sarin-like and soman-like organophosphorous agents on MAPK and JNK in rat brains"Forensic Sci. Int.. 112(2/3). 171-178 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada Y., Takatori T., Nagao M. et al.: "Expression of paraoxonase isoform did not confer protection from acute sarin poisoning in the Tokyo subway terrorist attack"Int J Legal Med.. 115(2). 82-84 (2001)

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

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Published: 2003-09-17  

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