Local Acetaldehyde: Its Key Role in Alcohol-Related Oropharyngeal Cancer

Abstract

Background: 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.

Summary: The strongest evidence for the local carcinogenicity of ACH in man provides a point mutation in the aldehyde dehydrogenase 2 (ALDH2) 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.

Key message: ALDH2 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.

Responses: 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.

Keywords: ALDH2; Acetaldehyde; Alcohol; Cancer; Oropharynx.

Fig. 1

Instant and long-term salivary ACH formation from ethanol after a dose of ­alcohol. Gray columns, microbial ACH formation; black column, excess ACH in ALDH2-deficients compared to that of ­ALDH2-actives.

Fig. 2

Effect of alcohol on the approximated local ACH exposure (mg/L × min/day) in relation to increased oropharyngeal cancer risk (OR/RR). ACH¹ (white circle), mean instant ACH exposure via saliva after one dose of 40% alcohol (Table 1); excess ACH² (gray and black circles); mean long-term exposure to excess salivary ACH in ALDH2-deficients compared to that of ­ALDH2-actives (Table 2).