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.
Stein
Scott
S
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794, USA.
Lao
Yanbin
Y
Yang
In-Young
IY
Hecht
Stephen S
SS
Moriya
Masaaki
M
D000079:Acetaldehyde / Q000378:metabolism / Q000633:toxicity*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009153:Mutagens; D009841:Oligonucleotides / Q000737:chemistry / Q000302:isolation & purification; D010957:Plasmids; D017354:Point Mutation; D013237:Stereoisomerism; D014162:Transfection; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism
D000447:Aldehydes; D018736:DNA Adducts; D009153:Mutagens; D009841:Oligonucleotides; C060934:1,N(2)-propanodeoxyguanosine; C012796:2-butenal; D003849:Deoxyguanosine; D000079:Acetaldehyde