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：醛脱氢酶2（ALDH2）将乙醇与乙酸产生的乙醛代谢，并在体内氧化中起主要作用。一半的日本人没有活性的ALDH2。我们通过基因靶向基因产生了ALDH2 NULL（ALDH2 KO）小鼠。为了研究乙醛的诱变性，在Aldh2 KO小鼠中进行了微核（MN）测定和T细胞受体（TCR）基因突变测定法，野生型（AldH2 wt）小鼠暴露于乙醛或乙醇中的乙醇中，源自乙醇：Acethode Hymetheyde：actefe verfo verfo verf a actefe vearf a varf a varf a a varf a a varf a a varor bairory verror baor bairory niber in acetef a a care baimetal dife bae vear baimetal dife n a vear baimentalde。进入由不锈钢制成的曝光室（第100升）的顶部。将小鼠连续暴露于500ppm乙醛蒸气或100mg/kg PO中。在暴露后，处死小鼠，并通过流膜仪测量微核网状细胞的频率。我们还观察到通过测量通过流胞度仪测量变异CD3^-4^+表达来评估的TCR基因突变的发生率：网状细胞中微核细胞中微核细胞中的频率显着增加，而Aldh2 KO小鼠中的乙醛暴露在Aldh2 KO中，但不在AldH2 KO中，但不在AldH2中，但不在此外，ALDH2 KO小鼠的尿液中尿液中尿液中的微核，TCR突变和8-羟基-2'-脱氧的鸟苷（8OHDG）的频率也明显高于对照组的ALDH2 WT小鼠。我们还观察到以100mg/kg的剂量给予乙醛的AldH2 KO小鼠中TCR突变的增加：在MN分析中，Aldh2 KO小鼠在暴露于Aldh2 wt小鼠时表现出较高的敏感性，当时暴露于Aldh2 wt小鼠。这意味着没有ALDH活性的酒精饮用者会增加癌变的风险。与ALDH2 WT小鼠相比，ALDH2 KO小鼠在MN和TCR基因突变中也显示出明显高的。这些结果表明，ALDH2不仅在乙醛解毒毒素中，而且在小鼠的氧化应激中起着重要作用。