linoleic-acid and 2-butenal

Results obtained in a number of studies in vitro and in vivo support the hypothesis that short- and long-chain enals and their epoxides derived from oxidized polyunsaturated fatty acids are potential endogenous sources of cyclic propano and etheno DNA adducts. We previously reviewed the evidence from some of these studies. Here, we describe the results of our more recent studies on the role of 1,N2-propanodeoxyguanosine adducts as endogenous DNA lesions. These studies include: the detection of distinct patterns of such adducts in various tissues of different species; the detection of long-chain trans-4-hydroxynonenal-derived deoxyguanosine adducts in vivo; the specificity of the formation of enal-derived propano adducts from omega-3 and omega-6 polyunsaturated fatty acids; and the detection of acrolein- and crotonaldehyde-derived adducts in human oral tissue DNA and their increased levels in smokers. Taken together, these studies further strengthen the hypothesis that enals produced by lipid peroxidation are the primary source for cyclic propano adducts in vivo, but these results cannot rule out the possible contribution of environmental and other sources. The mutagenicity of enals and their epoxides and the results of site-specific mutagenesis studies indicate that the cyclic adducts are potential promutagenic lesions; however, only circumstantial evidence is currently available for their role in carcinogenesis.

Topics: Acrolein; Aldehydes; Animals; Arachidonic Acid; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA; DNA Adducts; DNA Damage; Docosahexaenoic Acids; Fatty Acids; Glutathione; Humans; Linoleic Acid; Lipid Peroxidation; Mice; Models, Chemical; Rats

Inflammation-related reactive oxygen species (ROS) and reactive nitrogen species (RNS) are associated with the development of cancer. ROS and RNS can directly damage biomacromolecules such as proteins, DNA, and lipids. Lipid peroxidation, however, can result in reactive carbonyl species (RCS) that can also modify proteins and DNA. In contrast to an extensive literature on the modification of proteins and DNA from omega-6 fatty acids, there are few studies on RCS generation from other fatty acids, particularly omega-3 fatty acids, which are frequently consumed from the diet and diet supplements. Therefore, a comparison between omega-3 and omega-6 fatty acids has been conducted. LC-MS/MS analysis of carbonyl-dinitrophenylhydrazine (DNPH) standards yielded characteristic fragment ions. Autoxidation products of α-linolenic acid and linoleic acid were then derivatized with DNPH and analyzed by LC-MS/MS. The results showed that α-linolenic acid, an omega-3 fatty acid, generated more acrolein and crotonaldehyde than did linoleic acid, an omega-6 fatty acid. Omega-3 fatty acids might be easily degraded to smaller monoaldehydes or dicarbonyls. Omega-3 fatty acids have been considered as health improvement components for a long time. However, on the basis of the results presented here, use of omega-3 fatty acids should be re-evaluated in vivo for safety purposes.

Topics: Acrolein; Aldehydes; alpha-Linolenic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Linoleic Acid; Lipid Peroxidation; Oxidation-Reduction

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.

Topics: Acrolein; Aldehydes; alpha-Linolenic Acid; Arachidonic Acid; Chromatography, High Pressure Liquid; Deoxyguanine Nucleotides; Deoxyguanosine; DNA Adducts; DNA Damage; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Linoleic Acid; Oxidation-Reduction; Stearic Acids