The
cyclic 1,N(2)-propanodeoxyguanosine adducts, derived from alpha,beta-unsaturated
aldehydes or enals, including
acrolein (Acr),
crotonaldehyde (Cro), and trans-4-hydroxy-2-nonenal (HNE), have been detected as endogenous DNA lesions in rodent and human tissues. Collective evidence has indicated that the oxidative metabolism of
polyunsaturated fatty acids (PUFAs) is an important pathway for endogenous formation of these adducts. In a recent study, we examined the specific role of different types of
fatty acids, omega-3 and omega-6 PUFAs, in the formation of cyclic adducts of Acr, Cro, and HNE. Our studies showed that the incubation of
deoxyguanosine 5'-monophosphate with omega-3 or
omega-6 fatty acids under oxidative conditions in the presence of
ferrous sulfate yielded different amounts of Acr, Cro, and HNE adducts, depending on the types of
fatty acids. We observed that Acr- and Cro-dG adducts are primarily formed from omega-3, and the adducts derived from longer chain enals, such as HNE, were detected exclusively from
omega-6 fatty acids. Acr adducts are also formed from
omega-6 fatty acids, but to a lesser extent; the yields of Acr adducts are proportional to the number of double bonds present in the PUFAs. Two previously unknown cyclic adducts, one from pentenal and the other from heptenal, were detected as products from omega-3 and
omega-6 fatty acids, respectively. Because omega-6 PUFAs are known to be involved in the promotion of
tumorigenesis, we investigated the role of HNE adducts in p53 gene mutation by mapping the HNE binding to the human p53 gene with
UvrABC nuclease and determined the formation of HNE-dG adducts in the gene. The results showed that HNE-dG adducts are preferentially formed in a sequence-specific manner at the third base of
codon 249 in the p53 gene, a mutational hotspot in human
cancers. The DNA repair study using plasmid
DNA containing HNE-dG adducts as a substrate in HeLa cell extracts showed that HNE adducts are readily repaired, and that nucleotide excision repair appears to be a major pathway involved. Together, results of these studies provide a better understanding of the involvement of different PUFAs in DNA damage and their possible roles in
tumorigenesis.