Seitz H K, Pöschl G, Simanowski U A
Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, Heidelberg, Germany.
Recent Dev Alcohol. 1998;14:67-95. doi: 10.1007/0-306-47148-5_4.
A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.
大量流行病学数据已证实，长期饮酒是上消化道癌症（包括口咽癌、喉癌和食管癌）以及肝癌的重要危险因素。与这些器官不同，饮酒增加大肠和乳腺癌发病风险的程度要小得多。然而，尽管风险较低，但相对低剂量的乙醇每日摄入仍可促进致癌作用。鉴于这些肿瘤的高发病率，即使癌症风险有小幅增加也非常重要，尤其是对于那些因其他原因而具有较高风险的个体。关于酒精与其他器官癌症的流行病学数据存在争议，目前尚无足够证据证明存在显著关联。尽管尚不清楚长期饮酒刺激致癌的确切机制，但动物实验研究支持这样的观点：乙醇本身不是致癌物，但在某些实验条件下是一种促癌剂和/或（尤其是在肝脏中）肿瘤促进剂。乙醇代谢会产生乙醛和自由基。这些高反应性化合物会迅速与细胞成分结合，甚至可能与DNA结合。乙醛会降低DNA修复机制以及DNA中胞嘧啶的甲基化。它还会消耗谷胱甘肽，这是解毒过程中的一种重要肽。此外，它会导致染色体畸变，似乎与组织损伤和继发性代偿性过度再生有关。最近，有报道称胃肠道细菌会大量产生乙醛。酒精刺激致癌的其他机制包括诱导细胞色素P4502E1，这与酒精饮料中、与烟草烟雾以及饮食中存在的各种前致癌物的活化增强有关，致癌物代谢和分布的改变，细胞周期行为的改变（如细胞周期持续时间导致过度再生），营养缺乏（如甲基、维生素A、叶酸、磷酸吡哆醛、锌和硒缺乏）以及免疫系统的改变，最终导致对某些病毒感染（如乙型肝炎病毒和丙型肝炎病毒）的易感性增加。此外，上消化道和直肠的局部机制可能尤为重要。这些机制会导致组织损伤，如肝硬化，这是肝细胞癌的一个主要先决条件。因此，所有这些机制协同作用，积极调节致癌作用，从而促进癌症发生。
