The role of expression and polymorphism of metabolic enzymes in the smoking-or alcohol-induced carcinogenesis of the esophagus and the lung

吸烟和饮酒等环境因素在肺癌和食管癌的发展中很重要。大多数致癌物本身不是致癌物，需要代谢活化才能作为致癌物。因此，据报道，激活或解毒的代谢酶在外源性诱导的致癌作用中起重要作用。这些代谢酶的多态性被认为与这些癌症的易感性有关。例如，失活的醛脱氢酶2（ALDH 2）是食管癌的危险因素。为了阐明这些酶表达的作用以及危险因素的分子靶点，我们进行了研究。1)ALDH 2的表达与饮酒状态、饮酒后脸红密切相关。因此，ALDH 2的遗传状态以及饮酒量对ALDH 2在食管中的表达一定是重要的。2)为了评估Aldh 2缺失小鼠的有用性，检查了野生小鼠中ALDH 2的组织分布，发现其与人的组织分布相似。因此，Aldh 2-null小鼠被认为是用于研究酒精代谢和相关疾病的有用的模型动物。3)正常食管中的Fhit丢失与饮酒习惯以及食管癌的多样性密切相关。4)在肺癌方面，p63甲基化在重度吸烟者和鳞状细胞癌患者中经常观察到。因此，p16基因甲基化可能在吸烟诱发的肺癌发生中起重要作用。

Environmental factors such as cigarette smoking and alcohol drinking are important in the development of lung cancer as well as esophageal cancer. Most carcinogens are not carcinogenic per se, and the metabolic activation is required to act as carcinogens. Therefore, metabolic enzymes to activate or detoxify are reported to play an important role in exogenously induced carcinogenesis. The polymorphism of these metabolic enzymes is considered to be associated with susceptibility to these cancers. For example, inactive aldehyde dehydrogenase 2 (ALDH2) is a risk factor of esophageal cancer. In order to clarify the role of the expression of these enzymes as well as the molecular targets of risk factors, we have performed researches. 1) The expression of ALDH2 was closely associated with drinking status and flushing after drinking. Therefore, the genetic status of ALDH2 as well as alcohol consumption must be important in the expression of ALDH2 in the esophagus. 2) In order to evaluate the usefulness of Aldh2-null mice, the tissue-distribution of ALDH2 in wild mice was examined and it found to be similar with that of human. Therefore, Aldh2-null mice are considered to be useful model animals for investigation of alcohol metabolism and related diseases. 3) Fhit loss in the normal esophagus is closely associated with drinking habits as well as multiplicity of esophageal cancer. 4) Regarding lung cancer, the methylation of p63 were frequently observed in heavy smoker and patients with squamous cell carcinoma. Therefore, methylation of p 16 may play an important role in smoking-induced lung carcinogenesis.