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Reaction mechanisms and evaluation of toxicity of the formation of nitric oxide from UVA-irradiated N-nitroso-compound

UVA照射N-亚硝基化合物形成一氧化氮的反应机理及毒性评价

基本信息

批准号：
15510053
负责人：
ARIMOTO Sakae
金额：
$ 2.43万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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.

N-亚硝基脯氨酸（NPRO）是由脯氨酸和亚硝酸盐内源形成的。据报告，NPRO无致突变性和致癌性。我们发现NPRO加自然日光对鼠伤寒沙门氏菌和噬菌体M13 mp2的直接致突变性。大多数诱导的序列变化是GC到TA和GC到CG的颠换。这表明鸟嘌呤残基的修饰是这些颠换的原因。本文探讨了UVA照射NPRO溶液中一氧化氮（NO）的生成。我们分析了突变和NO形成的光动力学光谱，使用300 nm和400 nm之间的单色辐射。突变频率和NO生成曲线与NPRO的吸收曲线一致。NPRO和UVA的协同致突变作用是UVA辐射致癌风险增加的可能机制，烟草特有的亚硝胺4-（N-甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）通过微粒体代谢产生突变。我们发现在不存在代谢活化的情况下，NNK与UVA在艾姆斯细菌和噬菌体M13 mp2中的直接作用致突变性。诱发突变以GC → CG、GC → TA和GC → AT为主。经NNK和UVA处理的小牛胸腺DNA，其8 oxodG/dG和06 meG/G的量较未处理的对照组增加。DNA链断裂观察NNK和UVA处理后，并抑制在存在的氧和NO自由基的清除剂。在用UVA照射的NNK溶液中也观察到NO的形成。突变诱导、8 oxodG形成和NO形成的图与NNK的吸收曲线对齐。我们的结论是，NNK可能作为光敏剂响应UVA产生NO和其他氧化和烷基化的中间体后，在DNA中形成8-oxodG和O 6 meG，这可能会导致突变和DNA链断裂。