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道癌的发生中起着重要作用。大多数致癌物本身并不致癌，代谢激活才能起到致癌物的作用。因此，据报道，代谢酶激活或解毒在外源性致癌中起着重要作用。这些代谢酶的多态被认为与这些癌症的易感性有关。例如，失活的乙醛脱氢酶2(ALDH2)是食道癌的危险因素。为了阐明这些酶的表达作用以及危险因素的分子靶点，我们进行了研究。1)ALDH2的表达与饮酒状态和饮酒后潮红密切相关。因此，ALDH2的遗传状态和饮酒对ALDH2在食道中的表达必须是重要的。2)研究了ALDH2基因在野生型小鼠体内的组织分布，发现ALDH2基因在野生型小鼠体内的分布与人类相似，以评价ALDH2基因缺失型小鼠的应用价值。因此，ALDH2基因缺失小鼠被认为是研究酒精代谢及相关疾病的有用模型动物。3)正常食道的FHIT丢失与饮酒习惯及食道癌的多发性密切相关。4)在肺癌方面，重度吸烟者和鳞癌患者中p63基因甲基化的发生率较高。因此，p16基因甲基化可能在吸烟诱导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.