2001 Fiscal Year Final Research Report Summary
The study on non-cholinergic toxicity of Nerve agents
| Project/Area Number |
11670408
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Legal medicine
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| Research Institution | Nagoya City University |
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Principal Investigator |
NAGAO Nasataka Nagoya City University Medical School, Professor, 医学部, 教授 (80227991)
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| 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)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Sarin / Soman / organophosphorous agent / rat / brain / PLCγ / MAPK / JNK / paraoxonase |
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| 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.
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