The role of acetaldehyde in alcohol-associated cancer of the gastrointestinal tract.
Acetaldehyde has been classified as a carcinogen in experimental animal research. Acetaldehyde is highly toxic, mutagenic and carcinogenic. Acetaldehyde causes point mutations, sister chromatid exchanges and gross chromosomal aberrations. In the liver, acetaldehyde binds to DNA and the formation of stable adducts represents one mechanism by which acetaldehyde could trigger the occurrence of replication errors and/or mutations in oncogenes or tumour suppressor genes. In experimental colorectal carcinogenesis the inhibition of acetaldehyde dehydrogenase with elevated acetaldehyde levels results in an acceleration of cancer development. The production of acetaldehyde is reduced when germ-free animals are studied, emphasizing the role of bacteria in the generation of colorectal acetaldehyde. Acetaldehyde levels in the colorectum correlate with crypt cell production rate and result in hyper-regeneration, a precancerous condition. Genetic linkage studies give further evidence for acetaldehyde as a carcinogen. Individuals who accumulate acetaldehyde due to polymorphism and/or mutations in the genes coding for enzymes responsible for acetaldehyde generation and detoxification have an increased cancer risk. This is true for Asians with low acetaldehyde dehydrogenase 2 and for Caucasians with alcohol dehydrogenase 1C*1/1. In conclusion, there is an enormous body of evidence from in vitro studies, animal experiments and genetic linkage studies, that acetaldehyde is the major factor responsible for tumour development in alcohol-associated carcinogenesis of the gastrointestinal tract.
Seitz
Helmut K
HK
Laboratory of Alcohol Research, Liver Disease and Nutrition, Department of Medicine, Salem Medical Center Heidelberg and University of Heidelberg, Heidelberg, Germany.
Homann
Nils
N
D000079:Acetaldehyde / Q000378:metabolism* / Q000633:toxicity*; D000428:Alcohol Drinking / Q000009:adverse effects*; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002273:Carcinogens / Q000633:toxicity*; D004261:DNA Replication / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D005770:Gastrointestinal Neoplasms / Q000139:chemically induced*; D008040:Genetic Linkage; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000187:drug effects; D012307:Risk Factors
D002273:Carcinogens; D000431:Ethanol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde