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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（ALDH 2）将乙醇产生的乙醛代谢为乙酸，并在体内乙醛氧化中起主要作用。一半的日本人有不活跃的ALDH 2。我们通过基因靶向敲除产生Aldh 2 null（Aldh 2 KO）小鼠。为了研究乙醛的致突变性，采用Aldh 2 KO小鼠和野生型小鼠（Aldh 2 WT），分别进行了乙醛和乙醇的体内微核（MN）试验和T细胞受体（TCR）基因突变试验。小鼠经口染毒500 ppm乙醛蒸气或100 mg/kg乙醛，连续两周。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。结果：乙醛暴露可显著增加Aldh 2 KO小鼠网织红细胞微核率，但对Aldh 2 WT小鼠无显著影响。此外，即使在对照组中，Aldh 2 KO小鼠的微核、TCR突变频率和尿液中8-羟基-2 '-脱氧鸟苷（8 OHdG）水平也显着高于Aldh 2 WT小鼠。我们还观察到以100 mg/kg剂量给予乙醛的Aldh 2 KO小鼠中TCR突变的增加。讨论：在MN测定中，当暴露于乙醛时，与Aldh 2 WT小鼠相比，Aldh 2 KO小鼠显示出高敏感性。这意味着没有ALDH活性的饮酒者会增加致癌的风险。即使在对照中，与Aldh 2 WT小鼠相比，Aldh 2 KO小鼠也显示出显著高的MN和TCR基因突变。这些结果表明，Aldh 2不仅在乙醛解毒中起重要作用，而且在小鼠的氧化应激中也起重要作用。