ADH1B*2/ALDH2*2 多态性的联合改变了日本酗酒者血液中乙醛衍生的 DNA 损伤。
Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of Japanese alcoholics.
机构信息
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Japan.
出版信息
Cancer Sci. 2012 Sep;103(9):1651-5. doi: 10.1111/j.1349-7006.2012.02360.x. Epub 2012 Jul 24.
The acetaldehyde associated with alcoholic beverages is an evident carcinogen for the esophagus. Genetic polymorphisms of the alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes are associated with the risk of esophageal cancer. However, the exact mechanism via which these genetic polymorphisms affect esophageal carcinogenesis has not been elucidated. ADH1B2 is involved in overproduction of acetaldehyde due to increased ethanol metabolism into acetaldehyde, and ALDH22 is involved in accumulation of acetaldehyde due to the deficiency of acetaldehyde metabolism. Acetaldehyde can interact with DNA and form DNA adducts, resulting in DNA damage. N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) is the most abundant DNA adduct derived from acetaldehyde. Therefore, we quantified N(2)-ethylidene-dG levels in blood samples from 66 Japanese alcoholic patients using liquid chromatography/electrospray tandem mass spectrometry, and investigated the relationship between N(2)-ethylidene-dG levels and ADH1B and ALDH2 genotypes. The median N(2)-ethylidene-dG levels (25th percentile, 75th percentile) in patients with ADH1B1/1 plus ALDH21/1, ADH1B2 carrier plus ALDH21/1, ADH1B1/1 plus ALDH21/2, and ADH1B2 carrier plus ALDH21/2 were 2.14 (0.97, 2.37)/10(7) bases, 2.38 (1.18, 2.98)/10(7) bases, 5.38 (3.19, 6.52)/10(7) bases, and 21.04 (12.75, 34.80)/10(7) bases, respectively. In the ALDH21/2 group, N(2)-ethylidene-dG levels were significantly higher in ADH1B2 carriers than in the ADH1B1/1 group (P < 0.01). N(2)-ethylidene-dG levels were significantly higher in the ALDH21/2 group than in the ALDH21/1 group, regardless of ADH1B genotype (ADH1B1/1, P < 0.05; ADH1B2 carriers, P < 0.01) N(2)-ethylidene-dG levels in blood DNA of the alcoholics was remarkably higher in individuals with a combination of the ADH1B2 and ALDH22 alleles. These results provide a new perspective on the carcinogenicity of the acetaldehyde associated with alcoholic beverages, from the aspect of DNA damage.
酒精饮料中所含的乙醛是食管的明显致癌物质。乙醇脱氢酶 1B（ADH1B）和醛脱氢酶 2（ALDH2）基因的遗传多态性与食管癌的风险相关。然而，这些遗传多态性影响食管癌发生的确切机制尚未阐明。ADH1B2 导致乙醛过量产生，因为乙醇代谢为乙醛增加，而 ALDH22 导致乙醛代谢不足，导致乙醛积累。乙醛可以与 DNA 相互作用形成 DNA 加合物，导致 DNA 损伤。N(2)-乙基-2'-脱氧鸟苷（N(2)-ethylidene-dG）是源自乙醛的最丰富的 DNA 加合物。因此，我们使用液相色谱/电喷雾串联质谱法对 66 名日本酒精患者的血液样本中的 N(2)-乙基-dG 水平进行了定量，并研究了 N(2)-乙基-dG 水平与 ADH1B 和 ALDH2 基因型之间的关系。ADH1B1/1 加 ALDH21/1、ADH1B2 携带者加 ALDH21/1、ADH1B1/1 加 ALDH21/2 和 ADH1B2 携带者加 ALDH21/2 患者的 N(2)-乙基-dG 水平（中位数[25 百分位数，75 百分位数]）分别为 2.14（0.97，2.37）/10(7) 个碱基、2.38（1.18，2.98）/10(7) 个碱基、5.38（3.19，6.52）/10(7) 个碱基和 21.04（12.75，34.80）/10(7) 个碱基。在 ALDH21/2 组中，ADH1B2 携带者的 N(2)-乙基-dG 水平明显高于 ADH1B1/1 组（P<0.01）。无论 ADH1B 基因型如何（ADH1B1/1，P<0.05；ADH1B2 携带者，P<0.01），ALDH21/2 组的 N(2)-乙基-dG 水平均明显高于 ALDH21/1 组。酒精中毒者血液 DNA 中的 N(2)-乙基-dG 水平在同时携带 ADH1B2 和 ALDH22 等位基因的个体中显著升高。这些结果从 DNA 损伤的角度为与酒精饮料相关的乙醛的致癌性提供了新的视角。
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