Formation of cyclic deoxyguanosine adducts from omega-3 and omega-6 polyunsaturated fatty acids under oxidative conditions.
The discovery of the cyclic 1,N(2)-propanodeoxyguanosine adducts of acrolein (Acr), crotonaldehyde (Cro), and t-4-hydroxy-2-nonenal (HNE) as endogenous DNA lesions from lipid peroxidation has raised questions regarding the role of different types of fatty acids as sources for their formation. In this study, we carried out reactions at pH 7 and 37 degrees C with deoxyguanosine 5'-monophosphate and omega-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA), linolenic acid (LNA), and eicosapentaenoic acid (EPA); or omega-6 PUFAs, including linoleic acid (LA) and arachidonic acid (AA), each in the presence of ferrous sulfate. The formation of Acr, Cro, and HNE-derived 1,N(2)-propanodeoxyguanosine adducts (Acr-, Cro-, and HNE-dG) in the incubation mixture was determined by reversed-phase HPLC analysis. The results showed that Acr and Cro adducts are primarily derived from omega-3 PUFAs, although Acr adducts are also formed, to a lesser extent, from oxidized AA and LA. HNE-dG adducts were detected exclusively in incubations with AA. The kinetics of the formation of these adducts was determined during incubations for 2 weeks and 5 days. The rate of Acr adduct formation was about 5-10-fold that of Cro adducts, depending on the type of PUFAs, and the rate of formation of HNE adducts from AA was also considerably slower than that of Acr adducts. Unlike other cyclic adducts, the formation of Acr adducts was independent of types of PUFAs, but its yield was proportional to the number of double bonds in the fatty acid. Only one of the isomeric Acr adducts was detected, and its stereoselective formation is consistent with that observed previously in vivo. Two previously unknown cyclic adducts, one derived from pentenal and the other from heptenal, were also detected as products from omega-3 and omega-6 fatty acids, respectively. This study demonstrated the specificity for the formation of the cyclic adducts of Acr, Cro, and HNE and other related enals by oxidation of omega-3 and omega-6 PUFAs. These results may be important for the understanding of the specific roles of different types of fatty acids in tumorigenesis.
Pan
Jishen
J
Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595, USA.
Chung
Fung-Lung
FL
D000171:Acrolein / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D016718:Arachidonic Acid / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000138:chemical synthesis*; D004249:DNA Damage; D003848:Deoxyguanine Nucleotides / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D004281:Docosahexaenoic Acids / Q000737:chemistry; D015118:Eicosapentaenoic Acid / Q000737:chemistry; D015525:Fatty Acids, Omega-3 / Q000737:chemistry*; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D019787:Linoleic Acid / Q000737:chemistry; D010084:Oxidation-Reduction; D013229:Stearic Acids / Q000737:chemistry; D017962:alpha-Linolenic Acid / Q000737:chemistry
D000447:Aldehydes; D018736:DNA Adducts; D003848:Deoxyguanine Nucleotides; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D013229:Stearic Acids; D017962:alpha-Linolenic Acid; C060934:1,N(2)-propanodeoxyguanosine; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C031183:stearic acid; D000171:Acrolein; C012796:2-butenal; D019787:Linoleic Acid; D015118:Eicosapentaenoic Acid; D003849:Deoxyguanosine