[¹³C₂]- Acetaldehyde Promotes Unequivocal Formation of 1,N²-Propano-2′-deoxyguanosine in Human Cells

Acetaldehyde is an environmentally widespread genotoxic aldehyde present in tobacco smoke, vehicle exhaust and several food products. Endogenously, acetaldehyde is produced by the metabolic oxidation of ethanol by hepatic NAD-dependent alcohol dehydrogenase and during threonine catabolism. The formation of DNA adducts has been regarded as a critical factor in the mechanisms of acetaldehyde mutagenicity and carcinogenesis. Acetaldehyde reacts with 2′-deoxyguanosine in DNA to form primarily N²-ethylidene-2′-deoxyguanosine. The subsequent reaction of N²-ethylidenedGuo with another molecule of acetaldehyde gives rise to 1,N²-propano-2′-deoxyguanosine (1,N²-propanodGuo), an adduct also found as a product of the crotonaldehyde reaction with dGuo. However, adducts resulting from the reaction of more than one molecule of acetaldehyde in vivo are still controversial. In this study, the unequivocal formation of 1,N²-propanodGuo by acetaldehyde was assessed in human cells via treatment with [¹³C₂]-acetaldehyde. Detection of labeled 1,N²-propanodGuo was performed by HPLC/MS/MS. Upon acetaldehyde exposure (703 μM), increased levels of both 1,N²-etheno-2′-deoxyguanosine (1,N²-εdGuo), which is produced from α,β-unsaturated aldehydes formed during the lipid peroxidation process, and 1,N²-propanodGuo were observed. The unequivocal formation of 1,N²-propanodGuo in cells exposed to this aldehyde can be used to elucidate the mechanisms associated with acetaldehyde exposure and cancer risk.