Alcohol metabolism and cancer risk

Abstract

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.

Figure

Pathways of ethanol metabolism and their role in carcinogenesis. Ethanol is oxidized to acetaldehyde through the actions of various alcohol dehydrogenase (ADH) enzymes (e.g., enzymes encoded by the ADH1B and ADH1C genes), through the microsomal enzyme cytochrome P450 2E1 (CYP2E1), and by microbes living in the human gastrointestinal tract (e.g., mouth and colon). The relative contributions of these pathways and the differences in activity between enzymes encoded by different ADH1B and ADH1C alleles is represented by the thickness of the arrows. Acetaldehyde is oxidized to acetate primarily by the enzyme aldehyde dehydrogenase 2 (ALDH2). Again, the thickness of the arrows indicates the rate of acetaldehyde oxidation in people carrying two active ALDH2*1 alleles, one active ALDH2*1 and one inactive ALDH2*2 allele, or two inactive ALDH2*2 alleles, respectively. Cancer-inducing substances (i.e., carcinogens) generated during the various pathways of alcohol metabolism are highlighted. These include acetaldehyde; highly reactive, oxygen-containing compounds (reactive oxygen species [ROS]) generated by CYP2E1; and adducts formed by the interactions of acetaldehyde or ROS with DNA.