Genotoxicity of acetaldehyde- and crotonaldehyde-induced 1,N2-propanodeoxyguanosine DNA adducts in human cells.

Reaction of crotonaldehyde or two molecules of acetaldehyde with DNA generates 3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)one (2, Scheme 1), which occurs in (6R, 8R) and (6S, 8S) configurations (Fig. 1). These diastereomers were site-specifically incorporated into oligonucleotides, which were then inserted into a double-stranded DNA vector for genotoxicity studies. Modified DNA was introduced into human xeroderma pigmentosum A (XPA) cells to allow replication. Analysis of progeny plasmid revealed that these DNA adducts inhibit DNA synthesis to similar degrees. (6S, 8S)-2 miscodes more frequently than (6R, 8R)-2: 10% versus 5%. For both adducts, major miscoding events were G-->T transversions, but G-->A transitions were also observed at a comparable level for (6R, 8R)-2. G-->C transversions were the second most common events for (6S, 8S)-2. Comparison of these results with those of other 1,N2-propanodeoxyguanosine (PdG) adducts, which were evaluated by the same system, indicates that (i) their synthesis inhibiting potencies are stronger than that of the unsubstituted analog, 3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)one (1, Scheme 1), but weaker than that of 3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-6-hydroxypyrimido[1,2-a]purine-10(3H)one (3, Scheme 1); (ii) both isomers of 2 are more miscoding than 1; (iii) the miscoding potency of (6S, 8S)-2 is comparable to those of 3 and a model PdG 4 lacking a hydroxyl and a methyl group (Fig. 1). Therefore, considering the fact that 2 are formed endogenously as well as exogenously, they may play a significant role in aging and cancer in humans.