Evaluation of the alcohol-related cancer using aldehyde dehydrogenase 2 knock-out mice exposed to acetaldehyde or ethanol.

使用暴露于乙醛或乙醇的乙醛脱氢酶 2 敲除小鼠评估与酒精相关的癌症。

基本信息

批准号：
16310047
负责人：
KUNUGITA Naoki
金额：
$ 4.16万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Introduction : Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. Half of Japanese have inactive ALDH2. We generated Aldh2 null (Aldh2 KO) mice by gene targeting knockout. In order to investigate the mutagenicity of acetaldehyde, micronucleus (MN) assay and T cell receptor (TCR) gene mutation assay were performed in Aldh2 KO mice and wild type (Aldh2 WT) mice exposed to acetaldehyde or ethanol in vivo.Methods : Acetaldehyde vapor, obtained by a diffusion tube, was introduced into the top of an exposure chamber (volume 100 l) made of stainless steel. The mice were exposed to 500ppm acetaldehyde vapour or 100mg/kg po for two weeks continuously. Just after exposure, mice were sacrificed and the frequency of micronucleated reticulocytes was measured by flowcytometry. We also observed the incidence of TCR gene mutation in T-lymphocytes evaluated by measuring the variant CD3^-4^+ expression by flowcytometry.Results : Frequencies of micronuclei in reticulocytes significantly increased by acetaldehyde exposure in Aldh2 KO mice, but not in Aldh2 WT mice. In addition, frequencies of micronuclei, TCR mutation, and 8-hydroxy-2'-deoxyguanosine (8OHdG) levels in urine were significantly high in Aldh2 KO mice than in Aldh2 WT mice even in control groups. We also observed the increase of TCR mutation in Aldh2 KO mice administered acetaldehyde at the dose of 100mg/kg.Discussion : In the MN assay, Aldh2 KO mice showed the high sensitivity compared to Aldh2 WT mice, when exposed to acetaldehyde. It means that alcohol drinkers, who have no ALDH activity, increase the risk of carcinogenesis. Aldh2 KO mice also showed significantly high in MN and TCR gene mutation compared to Aldh2 WT mice even in control. These results indicate that Aldh2 plays a major role not only in acetaldehyde detoxification but also in oxidative stress in mice.

简介 : 乙醛脱氢酶-2 (ALDH2) 将乙醇产生的乙醛代谢为乙酸，并在体内乙醛的氧化中起主要作用。一半的日本人体内 ALDH2 不活跃。我们通过基因靶向敲除产生了 Aldh2 null (Aldh2 KO) 小鼠。为了研究乙醛的致突变性，对体内暴露于乙醛或乙醇的Aldh2 KO小鼠和野生型（Aldh2 WT）小鼠进行微核（MN）测定和T细胞受体（TCR）基因突变测定。方法：乙醛蒸气将通过扩散管获得的溶液引入由不锈钢制成的暴露室（体积100μl）的顶部。小鼠连续暴露于500ppm乙醛蒸气或100mg/kg口服2周。暴露后立即处死小鼠并通过流式细胞术测量微核网织红细胞的频率。我们还观察了 T 淋巴细胞中 TCR 基因突变的发生率，通过流式细胞术测量变体 CD3^-4^+ 表达来评估。结果：在 Aldh2 KO 小鼠中，乙醛暴露使网织红细胞中微核的频率显着增加，但在 Aldh2 WT 中则没有显着增加。老鼠。此外，即使在对照组中，Aldh2 KO 小鼠的微核频率、TCR 突变和尿液中 8-羟基-2'-脱氧鸟苷 (8OHdG) 水平也显着高于 Aldh2 WT 小鼠。我们还观察到以 100mg/kg 剂量乙醛给药的 Aldh2 KO 小鼠中 TCR 突变增加。讨论：在 MN 测定中，当暴露于乙醛时，Aldh2 KO 小鼠与 Aldh2 WT 小鼠相比表现出高敏感性。这意味着没有 ALDH 活性的饮酒者会增加致癌风险。即使在对照中，与 Aldh2 WT 小鼠相比，Aldh2 KO 小鼠也表现出显着较高的 MN 和 TCR 基因突变。这些结果表明 Aldh2 不仅在乙醛解毒中发挥着重要作用，而且在小鼠的氧化应激中也发挥着重要作用。