Acetaldehyde and the genome: Beyond nuclear DNA adducts and carcinogenesis

The designation of acetaldehyde associated with the consumption of alcoholic beverages as "carcinogenic to humans" (Group 1) by the International Agency for Research on Cancer (IARC) has brought renewed attention to the biological effects of acetaldehyde, as the primary oxidative metabolite of alcohol. Therefore, the overall focus of this review is on acetaldehyde and its direct and indirect effects on the nuclear and mitochondrial genome. We first consider different acetaldehyde-DNA adducts, including a critical assessment of the evidence supporting a role for acetaldehyde-DNA adducts in alcohol related carcinogenesis, and consideration of additional data needed to make a conclusion. We also review recent data on the role of the Fanconi anemia DNA repair pathway in protecting against acetaldehyde genotoxicity and carcinogenicity, as well as teratogenicity. We also review evidence from the older literature that acetaldehyde may impact the genome indirectly, via the formation of adducts with proteins that are themselves critically involved in the maintenance of genetic and epigenetic stability. Finally, we note the lack of information regarding acetaldehyde effects on the mitochondrial genome, which is notable since aldehyde dehydrogenase 2 (ALDH2), the primary acetaldehyde metabolic enzyme, is located in the mitochondrion, and roughly 30% of East Asian individuals are deficient in ALDH2 activity due to a genetic variant in the ALDH2 gene. In summary, a comprehensive understanding of all of the mechanisms by which acetaldehyde impacts the function of the genome has implications not only for alcohol and cancer, but types of alcohol related pathologies as well.