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.

Xylitol inhibits carcinogenic acetaldehyde production by Candida species

“…It reduced the production below the mutagenic acetaldehyde level of 40-100 lM for all Candida species tested. 2 In the absence of xylitol, the mean acetaldehyde production in ethanol incubation was high (220.5 lM). Xylitol has previously been shown to inhibit the metabolism of sugars by acidogenic oral bacteria and thus prevent tooth decay.…”

“…1 Mutagenicity can take place at concentrations as low as 40-100 lM of acetaldehyde. 2 Microbes possessing alcohol dehydrogenase (ADH) activity can produce acetaldehyde by ethanol oxidation. 3 This reaction takes place in the oral cavity when consuming alcohol and it continues for as long as there is ethanol in saliva.…”

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

“…ADH is present in almost every bodily tissue and actively metabolizes numerous aldehydic compounds. After ADH1B converts ethanol to acetaldehyde, it is further oxidized by Aldehyde Dehydrogenase (ALDH) isoenzymes to nontoxic acetate using NAD + as a cofactor [11][12][13][14][15][16][17]. Two immunologically distinct ALDH isoenzymes have been identified: Cytosolic ALDH1 and mitochondrial ALDH2.…”

Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

“…12,13 In this regard, acetaldehyde has also been classified as a bona fide chemical mutagen or carcinogen. Despite these findings, little is known about the interaction(s) of ethanol with the tumor microenvironment.…”