Reaction mechanisms and evaluation of toxicity of the formation of nitric oxide from UVA-irradiated N-nitroso-compound
| Project/Area Number |
15510053
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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 |
Risk sciences of radiation/Chemicals
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
ARIMOTO Sakae OKAYAMA UNIVERSITY, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, Associate professor, 大学院医歯薬学総合研究科, 助教授 (90212654)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Keinosuke OKAYAMA UNIVERSITY, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, professor, 大学院医歯薬学総合研究科, 教授 (70131183)
NEGASHI Tomoe OKAYAMA UNIVERSITY, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, Associate professor, 大学院医歯薬学総合研究科, 助教授 (80116491)
KIMURA Sachiko University of Hyogo, School of Human Science and Environment, Research associate, 環境人間学部, 助手 (70225035)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Ultraviolet light / N-nitroso compound / Nitric oxide / DNA damage / Deoxyguanosine adducts / Nitrosoproline / DNA alkylation / Oxidative DNA damage / タバコ特異的ニトロソアミン / マウス皮膚2段階発癌実験 / 8-ハイドロキシグアニン / マウス皮膚2段階発がん実験 |
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| Research Abstract |
N-Nitrosoproline (NPRO) is endogenously formed from proline and nitrite. NPRO had been reported to be nonmutagenic and noncarcinogenic. We discovered the direct mutagenicity of NPRO plus natural sunlight towards S.typhimurium and phage M13mp2. The majority of the induced sequence changes were GC to TA and GC to CG transversions. This suggested that modifications in guanine residues were responsible for these transversions. We explored the formation of nitric oxide (NO) in NPRO solution irradiated with UVA. We analyzed the photodynamic spectrum of mutation and NO formation using monochromatic radiation between 300 nm and 400 nm. The plots of mutation frequencies and NO formation were align with the absorption curve of NPRO. The co-mutagenic actions of NPRO and UVA merit attention as possible mechanisms increasing the carcinogenic risk from UVA irradiation.
The tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) undergoes-microsomal metabolism, giving rise to mutation. We discovered the directly acting mutagenicity of NNK with UVA in Ames bacteria and phage Ml3mp2 in the absence of metabolic activation. The majority of induced mutation were comprised of GC to CG, GC to TA and GC to AT. When calf thymus DNA was treated with NNK and UVA, the amount of 8oxodG/dG and O6meG/G increased compared with the untreated control. DNA strand breaks were observed following NNK and UVA treatment, and were suppressed in the presence of scavengers for oxygen and NO radical. The formation of NO was also observed in NNK solutions irradiated with UVA. The plots of mutation induction, 8oxodG formation and NO formation were align with the absorption curve of NNK. We conclude that NNK may act as a photosensitizer in response to UVA to produce NO and other oxidative and alkylative intermediates following the formation of 8-oxodG and O6meG in DNA, which may lead to mutations and DNA strand breaks.
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Report
(4 results)
Research Products
(22 results)
