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

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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.