Salaspuro Mikko
Research Unit on Acetaldehyde and Cancer, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
Visc Med. 2020 Jun;36(3):167-173. doi: 10.1159/000507234. Epub 2020 May 12.
Alcohol consumption and ethanol in alcoholic beverages are group 1 carcinogens, that is, carcinogenic to humans. However, ethanol itself is neither genotoxic nor mutagenic. Based on unique gene-epidemiologic and gene-biochemical evidence, the first metabolite of ethanol oxidation - acetaldehyde (ACH) - acts as a local carcinogen in the oropharynx. This review is focused on those facts, which highlight the importance of the oropharynx and local ACH in the pathogenesis of alcohol-related oropharyngeal cancer.
The strongest evidence for the local carcinogenicity of ACH in man provides a point mutation in the aldehyde dehydrogenase 2 () gene, which has randomized millions of alcohol consumers to markedly increased ACH exposure via saliva. This novel human cancer model is associated with manifold risk for oropharyngeal cancer and most importantly it is free from confounding factors markedly hampering epidemiological studies on alcohol-related cancer. The oropharynx is an ideal target organ for the cancer risk assessment of ACH. There is substantial epidemiological data on alcohol-related oropharyngeal cancer risk and also on salivary ACH concentrations among major risk groups for oropharyngeal cancer. Normal human saliva does not contain measurable levels of ACH. However, alcohol ingestion results within seconds in a concentration-dependent accumulation of ACH in saliva, which continues for up to 10-15 min after each sip of alcoholic beverage. This instant ACH exposure phase is followed by a long-term phase derived from ethanol diffused back to saliva from blood circulation. Microbes representing normal oral flora play a major role in local ACH formation from ethanol. In ALDH2-deficient subjects excess ACH during the long-term ACH exposure phase is most probably derived from salivary glands.
gene mutation proves the causal relationship between local ACH exposure via saliva and oropharyngeal cancer and provides new means for the quantitative assessment of local ACH exposure in relation to oropharyngeal cancer risk. Instant ACH formation from ethanol represents approximately 70-100% of total local ACH exposure. Ethanol present in "non-alcoholic" beverages and food forms an epidemiological bias in studies on alcohol-related upper digestive tract cancer.
One should quit smoking, adopt sensible drinking habits, and maintain good oral hygiene. Genetic risk groups could be screened and educated. Consumption of beverages and foodstuffs containing low ethanol levels as well as alcoholic beverages containing high ACH levels should be minimized. To that aim, labelling of alcohol and ACH concentrations of all beverages and foodstuffs should be mandatory.
酒精饮料中的酒精消费及乙醇属于第1类致癌物，即对人类致癌。然而，乙醇本身既无基因毒性也无致突变性。基于独特的基因流行病学和基因生物化学证据，乙醇氧化的首个代谢产物——乙醛（ACH）——在口咽中作为局部致癌物起作用。本综述聚焦于这些事实，它们突出了口咽及局部ACH在酒精相关口咽癌发病机制中的重要性。
ACH对人类具有局部致癌性的最有力证据是醛脱氢酶2（）基因中的一个点突变，该突变使数百万饮酒者因唾液而显著增加了ACH暴露。这个新的人类癌症模型与口咽癌的多种风险相关，最重要的是它没有明显妨碍酒精相关癌症流行病学研究的混杂因素。口咽是评估ACH癌症风险的理想靶器官。有大量关于酒精相关口咽癌风险以及口咽癌主要风险群体唾液中ACH浓度的数据。正常人类唾液中不含可测量水平的ACH。然而，饮酒后数秒内唾液中ACH会以浓度依赖的方式积累，每次饮用酒精饮料后这种积累会持续长达10 - 15分钟。这个即时ACH暴露阶段之后是一个长期阶段，该阶段的ACH来自从血液循环扩散回唾液的乙醇。代表正常口腔菌群的微生物在乙醇局部形成ACH过程中起主要作用。在ALDH2缺陷个体中，长期ACH暴露阶段的过量ACH很可能来自唾液腺。
基因突变证明了通过唾液局部暴露ACH与口咽癌之间的因果关系，并为定量评估与口咽癌风险相关的局部ACH暴露提供了新方法。乙醇即时形成的ACH约占局部ACH总暴露量的70 - 100%。“非酒精”饮料和食物中存在的乙醇在酒精相关上消化道癌研究中形成了一种流行病学偏差。
人们应戒烟，养成合理饮酒习惯，并保持良好的口腔卫生。可对遗传风险群体进行筛查和教育。应尽量减少饮用含低乙醇水平的饮料和食物以及含高ACH水平的酒精饮料。为此，应强制标注所有饮料和食物的酒精及ACH浓度。
