Increased DNA damage in ALDH2-deficient alcoholics
Increased DNA damage in ALDH2-deficient alcoholics
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DOI：
10.1021/tx060113h
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发表时间：
2006-10-16
影响因子：
4.1
通讯作者：
Yokoyama, Akira
中科院分区：
文献类型：
--
作者：
Matsuda, Tomonari;Yabushita, Hisatoshi;Yokoyama, Akira
饮酒是口腔癌、咽癌、喉癌和食道癌的危险因素。尽管许多研究表明乙醛（口服酒精的主要代谢物）在癌症发生中起着至关重要的作用，但乙醛脱氢酶 2 (ALDH2) 基因型与乙醛衍生的 DNA 损伤之间的联系尚未得到探索。我们开发了一种灵敏的定量方法，用于检测乙醛衍生的 DNA 加合物、N-2-乙基-2'-脱氧鸟苷 (N-2-Et-dG)、α-S-和 α-R-甲基-γ-羟基-1、N-2-丙烷-2'-脱氧鸟苷（α-S-Me-γ-OH-PdG 和 α-R-Me-γ-OH-PdG），以及N-2-(2,6-二甲基-1,3-二恶烷-4-基)-脱氧鸟苷 (N-2-Dio-dG)，采用液相色谱电喷雾串联质谱 (LC/ESI-MS/MS) 和稳定同位素内标测定。我们测定了来自日本酗酒患者的 44 份血液 DNA 样本中的 DNA 加合物。与 ALDH2* 1/2* 1 基因型的酗酒者相比，ALDH2* 1/2* 2 基因型的酗酒者中三种乙醛衍生的 DNA 加合物 N-2-Et-dG、α-S-Me-gamma-OH-PdG 和 α-R-Me-gamma-OH-PdG 的水平显着升高。在所分析的任何 DNA 样品中均未检测到 N-2-Dio-dG。这些结果提供了分子证据，证明 ALDH2 基因型影响乙醛引起的基因毒性损伤。
Drinking alcohol is a risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus. Although many studies suggest that acetaldehyde, a major metabolite of orally ingested alcohol, plays a crucial role in cancer initiation, the link between the aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage has not yet been explored. We have developed a sensitive and quantitative method for detecting the acetaldehyde- derived DNA adducts, N-2-ethyl-2'-deoxyguanosine (N-2-Et-dG), alpha-S-and alpha-R-methyl-gamma-hydroxy-1, N-2-propano-2'-deoxyguanosine (alpha-S-Me-gamma-OH-PdG and alpha-R-Me-gamma-OH-PdG), and N-2-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N-2-Dio-dG), by using liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) and stable-isotope internal standards. We determined the DNA adducts in 44 blood DNA samples from Japanese alcoholic patients. The levels of three acetaldehyde-derived DNA adducts, N-2-Et-dG, alpha-S-Me-gamma-OH-PdG, and alpha-R-Me-gamma-OH-PdG, were significantly higher in alcoholics with the ALDH2* 1/2* 2 genotype compared to those with the ALDH2* 1/2* 1 genotype. N-2-Dio-dG was not detected in any of the DNA samples analyzed. These results provide molecular evidence that the ALDH2 genotype affects the genotoxic damage caused by acetaldehyde.