Seitz Helmut K, Maurer Britta, Stickel Felix
Department of Medicine, Salem Medical Centre and Laboratory of Alcohol Research, Liver Disease and Nutrition, Heidelberg, Germany.
Dig Dis. 2005;23(3-4):297-303. doi: 10.1159/000090177.
Epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper gastrointestinal cancer (oropharynx, hypopharynx, esophagus) and colorectal cancer. Pathophysiological mechanisms include generation of acetaldehyde (AA) and reactive oxygen species (ROS), induction of cytochrome P 4502E1 (CYP2E1), and local and nutritional factors. Genetic polymorphisms of alcohol-metabolizing enzymes may individually influence the risk of carcinogenesis. AA, the first and major metabolite of ethanol, has proven to be the most carcinogenic and mutagenic agent in alcohol-associated cancer. Gastrointestinal bacteria as well as various isozymes of alcohol dehydrogenase (ADH) are capable of metabolizing ethanol to AA thus leading to an increased cell turnover of the gastrointestinal mucosa after chronic alcohol consumption. In Caucasians, ADH1C polymorphism is most important, for the ADH1C1 transcription results in an ADH isoenzyme 2.5 times more active than that from ADH1C2, which is associated with an increase in AA production. Additionally, oxidative stress due to an induction of CYP2E1 in the gastrointestinal mucosa of alcoholics should be considered as another key factor in alcohol-induced carcinogenesis. Nutritional deficiencies, i.e. lack of folic and retinoic acid, as well as malnutrition itself may also contribute to the development of gastrointestinal cancer.
流行病学数据已将长期饮酒确定为上消化道癌（口咽、下咽、食管）和结直肠癌的重要危险因素。病理生理机制包括乙醛（AA）和活性氧（ROS）的产生、细胞色素P 4502E1（CYP2E1）的诱导以及局部和营养因素。酒精代谢酶的基因多态性可能会分别影响致癌风险。AA是乙醇的首要和主要代谢产物，已被证明是酒精相关癌症中最具致癌性和致突变性的物质。胃肠道细菌以及酒精脱氢酶（ADH）的各种同工酶能够将乙醇代谢为AA，因此长期饮酒后会导致胃肠道黏膜细胞更新增加。在白种人中，ADH1C多态性最为重要，因为ADH1C1转录产生的ADH同工酶活性比ADH1C2产生的同工酶高2.5倍，这与AA生成增加有关。此外，酗酒者胃肠道黏膜中CYP2E1诱导引起的氧化应激应被视为酒精诱导致癌的另一个关键因素。营养缺乏，即缺乏叶酸和视黄酸，以及营养不良本身也可能导致胃肠道癌症的发生。
