Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism

Abstract

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.

Fig. 1

Ethanol metabolism and its role in carcinogenesis. Ethanol is metabolised via alcohol dehydrogenase (ADH) and via cytochrome P4502E1 (CYP2E1) to acetaldehyde. Acetaldehyde is further metabolised via acetaldehyde dehydrogenase (ALDH) to untoxic acetate. ADH1B and ADH1C show polymorphism with different enzyme kinetics and thus different acetaldehyde production. ALDH2 is mutated in Asians resulting in low enzyme activity and accumulation of acetaldehyde. Acetaldehyde is toxic, mutagenic and carcinogenic, results in DNA adducts, inhibits DNA repair and DNA methylation and damages the antioxidative defense system (AODS). In addition, ethanol oxidation via CYP2E1 also generates reactive oxygene species (ROS) which cannot be sufficiently detoxified due to an injured AODS and thus results in DNA adducts. CYP2E1 also activates various procarcinogens to their ultimative carcinogenic metabolites and metabolises retinoic acid resulting in low levels of hepatic retinoic acid