Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion.
Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion.
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发表时间：
2014-05
影响因子：
5.3
通讯作者：
Y. Yukawa;S. Ohashi;Y. Amanuma;Y. Nakai;Mihoko Tsurumaki;Osamu Kikuchi;S. Miyamoto;T. Oyama;T. Kawamoto;T. Chiba;T. Matsuda;M. Muto
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作者：
Y. Yukawa;S. Ohashi;Y. Amanuma;Y. Nakai;Mihoko Tsurumaki;Osamu Kikuchi;S. Miyamoto;T. Oyama;T. Kawamoto;T. Chiba;T. Matsuda;M. Muto
乙醇及其代谢产物乙醛是食管鳞状细胞癌（ESCC）的明确致癌物，而乙醛脱氢酶2（ALDH 2）的催化活性降低，使乙醛解毒，增加了ESCC的风险。然而，ALDH 2基因型是否影响乙醇摄入后食管中乙酰丙酮酸衍生的DNA损伤水平仍不清楚。在本研究中，我们口服或腹腔注射乙醇给Aldh 2基因敲除小鼠和对照小鼠，我们定量了食管中乙酰丙酮衍生的DNA损伤水平，特别是N（2）-亚乙基-2 '-脱氧鸟苷（N（2）-亚乙基-dG）。在口服乙醇给药模型中，Aldh 2基因敲除小鼠的食管N（2）-亚乙基-dG水平显著高于对照小鼠。类似地，在腹腔内乙醇给药模型中，其中食管未直接暴露于乙醇溶液，Aldh 2基因敲除小鼠的食管N（2）-亚乙基-dG水平也升高。该结果表明，循环乙醇衍生的乙醛导致食管DNA损伤，并且损伤程度受Aldh 2敲除的影响。综上所述，我们的研究结果强烈表明乙酰丙酮酸衍生的DNA损伤的重要性，这是在ALDH 2基因损伤的个体的食管中诱导的。这为理解酒精相关的食管癌发生提供了生理学基础。
Ethanol and its metabolite, acetaldehyde, are the definite carcinogens for esophageal squamous cell carcinoma (ESCC), and reduced catalytic activity of aldehyde dehydrogenase 2 (ALDH2), which detoxifies acetaldehyde, increases the risk for ESCC. However, it remains unknown whether the ALDH2 genotype influences the level of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. In the present study, we administered ethanol orally or intraperitoneally to Aldh2-knockout and control mice, and we quantified the level of acetaldehyde-derived DNA damage, especially N(2) -ethylidene-2'-deoxyguanosine (N(2) -ethylidene-dG), in the esophagus. In the model of oral ethanol administration, the esophageal N(2) -ethylidene-dG level was significantly higher in Aldh2-knockout mice compared with control mice. Similarly, in the model of intraperitoneal ethanol administration, in which the esophagus is not exposed directly to the alcohol solution, the esophageal N(2) -ethylidene-dG level was also elevated in Aldh2-knockout mice. This result indicates that circulating ethanol-derived acetaldehyde causes esophageal DNA damage, and that the extent of damage is influenced by knockout of Aldh2. Taken together, our findings strongly suggest the importance of acetaldehyde-derived DNA damage which is induced in the esophagus of individuals with ALDH2 gene impairment. This provides a physiological basis for understanding alcohol-related esophageal carcinogenesis.