2006 Fiscal Year Final Research Report Summary
Investigation of the mechanism of paraquat toxicity -Identification of the genes which are breakthrough for the toxicity-
| Project/Area Number |
16590552
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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 | Kawasaki Medical School |
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Principal Investigator |
TOMITA Masafumi Kawasaki Medical School, Medical Toxicology, Associate Professor, 医学部, 助教授 (50113197)
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| Co-Investigator(Kenkyū-buntansha) |
KATSUYAMA Hironobu Kawasaki Medical School, Public Health, Associate Professor, 医学部, 助教授 (00289175)
HIDAKA Kazuo Kawasaki Medical School, Biochemistry, Lecturer, 医学部, 講師 (00069064)
NISHIMATSU Shinichiro Kawasaki Medical School, Molecular Biology, Lecturer, 医学部, 講師 (20222185)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Paraquat / Toxicology / Gene expression / real-time PCR / Oxidative Stress / Lung fibrosis / Immunohistochemistry / Animal model |
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| Research Abstract |
We examined on gene expression levels to understand the mechanism of paraquat (PQ)-driven poisoning and the following results were obtained.
1) We examined the effect of PQ on the gene expression levels of antioxidant enzymes (AOE) and glutathione (GSH) status in lungs 16 h post-administration. Although GSH levels as well as some AOE expression levels were increased, GSH did not play as a OH radical scavenger because GSH peroxidase (GPX) was not stimulated.
2) Some genes related to oxidative stress, such as thioredoxin, GSH S-transferase, heme oxygenase 1(HO-1), NADPH-oxidoreductase 1 (NQO-1), showed a significant increase in their RNA expression at 3 h post-administration. Immunohistochemical analysis showed that HO-1 and NQO-1 were especially expressed in the bronchial epithelial cells of PQ-treated lung sections. In addition, the expression levels of some CYPs which are specific or dominant in female liver decreased markedly, while the male-specific CYPs showed an increase or no effec
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3) We obtained an increase of some genes in kidneys by 3 h after injection, and metallothionein-1 (MT-1) and HO-1 showed the biggest increase. However, the increases did not continue until 24 h after injection, and the second injection had less effect than the first. Up-regulation of these RNA levels was confirmed at the protein level. The MT-1 in kidneys had been consumed by the first injection. These results may explain the injury observed due to PQ uptake.
4) We developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution. The pathological progression of lung injury in this model was very similar to that of patients suffering from PQ poisoning.
5) Using the PQ-poisoned mouse model, we examined 45 gene expression levels at the initial destructive phase (within 5 days) that fibrosis has not completely developed. Some genes involved in inflammation and apoptosis showed the maximum increase within 1 day, while the genes involve in the development of fibrosis were significantly increased on day 5, not at 6 h nor at 24 h after PQ exposure. In addition, the RNA level of surfactant protein, EC-SOD, catalase decreased significantly time dependently. Less
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