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展中起着重要作用。大多数致癌物本身并不致癌，需要代谢激活才能起到致癌物的作用。因此，据报道，激活或解毒的代谢酶在外源性诱导的癌变中起重要作用。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 （ALDH2）是食管癌的一个危险因素。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酒后脸红密切相关。因此，ALDH2的遗传状态和酒精摄入在食道中ALDH2的表达中一定是重要的。2)为了评价ALDH2 -null小鼠的有效性，我们检测了野生小鼠中ALDH2的组织分布，发现其与人类相似。因此，aldh2缺失小鼠被认为是研究酒精代谢和相关疾病的有用模型动物。3)正常食道脂肪损失与饮酒习惯及食管癌的多样性密切相关。4)对于肺癌，p63的甲基化常见于重度吸烟者和鳞状细胞癌患者。因此，p16的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.