A possible photo sensitizer:: Tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induced mutations, DNA strand breaks and oxidative and methylative damage with UVA
A possible photo sensitizer:: Tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induced mutations, DNA strand breaks and oxidative and methylative damage with UVA
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DOI：
10.1016/j.mrgentox.2007.05.001
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发表时间：
2007-08-15
影响因子：
1.9
通讯作者：
Tanoue, Hiroyuki
中科院分区：
文献类型：
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作者：
Arimoto-Kobayashi, Sakae;Sakata, Hiroko;Tanoue, Hiroyuki
我们发现烟草特有的亚硝胺4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone(Nnk)对Ames细菌和噬菌体M13mp2具有直接作用的诱变性。我们研究了由UVA激活的NNK引起的突变谱。大多数(57%)的诱导序列改变是由GC到CG，GC到TA和GC到AT。这表明鸟嘌呤残基的修饰是导致这些突变的原因。因此，我们探索了DNA中7，8-二氢-8-氧代-2‘-脱氧鸟苷(8-oxodG)和O-6-甲基鸟嘌呤(O(6)Meg)的形成。当NNK和UVA处理小牛胸腺DNA时，DNA中8-oxodG/dG和O(6)Meg/G的含量分别比未处理的对照组增加20倍和100倍。在NNK和UVA处理后观察到DNA链断裂，并且在氧和NO自由基清除剂存在的情况下，链断裂被抑制。在经UVA照射的NNK液中也观察到了NO的生成。我们用单色辐射分析了突变诱导、8-oxodG形成和NO形成的光动力学光谱。作用光谱的模式与NNK的吸收光谱相似。我们的结论是，NNK可能作为光敏剂响应UVA，在DNA中形成8-oxodG和O6meG后产生NO和其他氧化和烷化中间产物，这可能导致突变和DNA链断裂。(C)2007 Elsevier B.V.保留所有权利。
We discovered the directly acting mutagenicity of the tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), with UVA light (320-400nm) in Ames bacteria and phage M13mp2 in the absence of metabolic activation. We have investigated the spectrum of mutations caused by UVA-activated NNK. The majority (57%) of induced sequence changes were comprised of GC to CG, GC to TA and GC to AT. This suggested that modification of guanine residues was responsible for these mutations. Hence, we explored the formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) and O-6-methylguanine (O(6)meG) in the DNA. When calf thymus DNA was treated with NNK and UVA, the amount of 8-oxodG/dG and O(6)meG/G in the DNA increased up to 20-fold and 100-fold, respectively, compared with the untreated control. DNA strand breaks were observed following NNK and UVA treatment, and the strand breaks 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. We analyzed the photodynamic spectrum of mutation induction, 8-oxodG formation and NO formation using monochromatic radiation. The patterns of the action spectra were comparable to the absorption spectrum 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. (c) 2007 Elsevier B.V. All rights reserved.