Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol
Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol
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DOI：
10.1093/carcin/bgm057
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发表时间：
2007-11-01
期刊：
影响因子：
4.7
通讯作者：
Ichiba, Masayoshi
中科院分区：
文献类型：
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作者：
Matsuda, Tomonari;Matsumoto, Akiko;Ichiba, Masayoshi
N-2-亚乙基-2'-脱氧鸟苷 (N-2-亚乙基-dG) 是乙醛诱导的主要 DNA 加合物。尽管它以核苷形式不稳定，但以 DNA 形式存在时相对稳定。在本研究中，我们分析了肝脏 DNA 中的三种乙醛衍生 DNA 加合物：N-2-亚乙基-dG、N-2-乙基-2'-脱氧鸟苷 (N-2-Et-dG) 和 α-甲基-γ-羟基-1,N-2-丙烷-2'-脱氧鸟苷 (α-Me-γ-OH-PdG)。 乙醛脱氢酶 (Aldh)-2 敲除小鼠，以确定饮酒和 Aldh2 基因型对 DNA 损伤水平的影响。在对照Aldh2+/+小鼠中，肝脏DNA中N-2-亚乙基-dG加合物的水平为每10(7)个碱基1.9+/-0.7个加合物，与Aldh2+/-和-/-小鼠没有显着差异。在酒精喂养的小鼠（20%乙醇5周）中，Aldh2+/+、+/-和-/-小鼠的加合物水平分别为每10(7)个碱基7.9+/-1.8、23.3+/-4.0和79.9+/-14.2个加合物，表明加合物水平依赖于酒精和Aldh2基因型。相比之下，α-Me-gamma-OH-PdG 没有观察到酒精或 Aldh2 基因型依赖性增加，并且在任何分析样品中都没有检测到 N-2-Et-dG。总之，在 Aldh2 缺陷人群中，模型动物肝脏体内形成 N-2-亚乙基-dG 的风险显着更高，这些结果可能有助于我们了解人类体内加合物形成。
N-2-ethylidene-2'-deoxyguanosine (N-2-ethylidene-dG) is a major DNA adduct induced by acetaldehyde. Although it is unstable in the nucleoside form, it is relatively stable when present in DNA. In this study, we analyzed three acetaldehyde-derived DNA adducts, N-2-ethylidene-dG, N-2-ethyl-2'-deoxyguanosine (N-2-Et-dG) and alpha-methyl-gamma-hydroxy-1,N-2-propano-2'-deoxyguanosine (alpha-Me-gamma-OH-PdG) in the liver DNA of aldehyde dehydrogenase (Aldh)-2-knockout mice to determine the influence of alcohol consumption and the Aldh2 genotype on the levels of DNA damage. In control Aldh2+/+ mice, the level of N-2-ethylidene-dG adduct in liver DNA was 1.9 +/- 0.7 adducts per 10(7) bases and was not significantly different than that of Aldh2+/- and -/- mice. In alcohol-fed mice (20% ethanol for 5 weeks), the adduct levels of Aldh2+/+, +/- and -/- mice were 7.9 +/- 1.8, 23.3 +/- 4.0 and 79.9 +/- 14.2 adducts per 10(7) bases, respectively, and indicated that adduct level was alcohol and Aldh2 genotype dependent. In contrast, an alcohol- or Aldh2 genotype-dependent increase was not observed for alpha-Me-gamma-OH-PdG, and N-2-Et-dG was not detected in any of the analyzed samples. In conclusion, the risk of formation of N-2-ethylidene-dG in model animal liver in vivo is significantly higher in the Aldh2-deficient population and these results may contribute to our understanding of in vivo adduct formation in humans.