Alcohol metabolism and cancer risk

Alcohol Research & Health, Wntr, 2007 by Helmut K. Seitz, Peter Becker

Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol-related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers. KEY WORDS: Alcohol and other drug (AOD) consumption; heavy drinking; chronic AOD use; ethanol metabolism; carcinogenesis; cancer; upper respiratory system cancer; oropharyngeal cancer; laryngeal cancer; aerodigestive tract cancer; esophageal cancer; liver cancer; colon cancer; colorectal cancer; breast cancer; acetaldehyde; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); genetic factors; cytochrome P450 2E1 (CYP2E1); reactive oxygen species

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Epidemiologic studies of the last decades have unequivocally identified chronic alcohol consumption as an important risk factor for the development (i.e., pathogenesis) of various types of cancers, including cancers of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon or rectum (i.e., colorectum), and breast (for a review, see Bagnardi et al. 2001). For these types of cancer, the following associations with alcohol consumption have been found:

* The highest cancer risk associated with alcohol consumption is seen for the upper aerodigestive tract--that is, the oral cavity, throat (i.e., pharynx), voice box (i.e., larynx), and esophagus. Heavy drinking (i.e., consumption of more than 80 g alcohol, or more than five to six drinks, per day (1)), especially combined with smoking, increases the risk of developing these cancers by a factor of 50 or more, depending on the population studied (Poschl and Seitz 2004).

* Alcohol-related liver cancer (i.e., hepatocellular carcinoma) primarily develops in people with liver cirrhosis resulting from chronic excessive alcohol use.

* The risk for alcohol-related colorectal and breast cancer is smaller than that for the upper aerodigestive tract cancer. However, because these types of cancer have a high prevalence in the Western world, alcohol likely is an important risk factor. One study (Longnecker 1994) calculated that 4 percent of all newly diagnosed breast cancer cases in the United States primarily result from alcohol consumption.

Overall, however, only a small percentage of chronic heavy drinkers develop certain types of cancer; moreover, some people develop cancer even at relative moderate daily alcohol consumption. These observations suggest that a genetic predisposition may influence cancer risk. At least part of this genetic predisposition may be related to alcohol metabolism because the rate of alcohol metabolism is genetically determined. Alcohol metabolism primarily involves three groups of enzymes (see Figure) (for more information on the pathways of alcohol metabolism, see Alcohol Research & Health Vol. 29, No. 4, "Alcohol Metabolism: Mechanisms of Action"):

* Alcohol dehydrogenase (ADH) enzymes that oxidize beverage alcohol (i.e., ethanol) to acetaldehyde.

* Aldehyde dehydrogenase (ALDH) enzymes that oxidize the acetaldehyde to acetate.

[FIGURE OMITTED]

* Cytochrome P450 2E1 (CYP2E1), a protein that is part of the microsomal ethanol oxidizing system (MEOS) and is involved in alcohol metabolism primarily after chronic alcohol consumption.

For several of these enzymes more than one genetic variant exists as follows (for more information, see the article by Edenberg, p. 5):

* Two of seven genes encoding ADH enzymes (i.e., the ADH1B and ADH1C genes) show polymorphism--that is, they exist in variants (i.e., alleles) that differ in their activities, resulting in the generation of different quantities of acetaldehyde.

* For the ALDH2 enzyme, the most important enzyme in the metabolism of acetaldehyde to acetate, two alleles exist, one of which has a very low activity, resulting in acetaldehyde accumulation after alcohol consumption; this genetic variant is present in a large proportion of Japanese and other East Asian people.