Studies by us and others have shown that the pro-mutagenic exocyclic propano, etheno, and malondialdehyde-derived adducts are endogenous DNA lesions in humans and rodents. Both in vitro and in vivo studies have provided substantial evidence supporting the role of enals generated by lipid peroxidation as sources for the formal of cyclic adducts. We showed that tissue glutathione (GSH) plays an important role in the protection against cyclic propano adduct formation. In addition to the cyclic propanodeoxyguanosine adducts derived from acrolein and crotonaldehyde (Acr-dG and Cro-dG, respectively). In addition to the cyclic propanodeoxyguanosine adducts derived from acrolein and crotonaldehyde (Acr-dG and Cro-dG, respectively), we recently detected in human and rodent tissues, including colon, the propanodeoxyguanosine adducts of 4-hydroxy-2-nonenal (HNE-dG), a long major long chain and rodent tissues, including colon, the propanodeoxyguanosine adducts of 4- hydroxy-2-nonenal (HNE-dG), a major long chain enal product of lipid peroxidation. Our in vitro experiments shown that Acr-dG and Cro-dG are products of omega-3 docosahexaenoic acid, whereas HNE-dG is exclusively from omega-6 fatty acids, such as linoleic acid and arachidonic acid. Therefore, it appears that the formal of cyclic adducts is dependent on types of fatty acids. We hypothesize that the formation of specific cyclic adducts is influenced by the dietary content of omega-3 and omega6 fatty acids and the long chain HNE-derived adducts are prominent lesions in colon DNA from omega-6 fatty acids and the long chain HNE- derived adducts are prominent lesions in colon DNA from omega-6 fatty acids. We also hypothesize that HNE and its epoxide promote colon tumorigenesis by forming the long-chain cyclic adducts caused by omega-6 fatty acids and glutathione (GSH) acts as an endogenous antioxidant in the protection against their formation. These hypotheses will be tested by carrying out the following studies:
Aim 1, Further Characterize the specificity of cyclic formation by omega-3 versus omega-6 fatty acids under in vitro oxidative conditions;
Aim 2, Examine specific changes in the levels and pattern of cyclic adducts in the colon DNA of rats treated by intra-rectal administration (topical appreciation to the colon) with the hydroperoxides of omega-3 and omega-6 fatty acids and their corresponding enal products;
Aim 3, Carry out tumor bioassay to determine whether HNE and its epoxide (EH) promote colon tumorigenesis in F344 rats;
Aim 4, Examine changes in the cyclic adduct levels and pattern in human colonic tissues obtained from an intervention study conducted at the Rockefeller University Hospital using different types of dietary fats;
Aim 5, Examine the role of GSH in enal-derived propano adduction by studying reaction of GSH-enal conjugates with dG and DNA and examining effect of antioxidant on adduct formation in L-buthionine (S,R)-sulfoximine (BSO)-treated rats;
Aim 6, Develop a gas chromatography/negative ion chemical ionization/mass spectrometry (GC/NICI/MS) assay for the detection of the propano dG adducts in DNA;
and Aim 7, Continue effort toward in vivo detection of cyclic adducts from other minor enal products of lipid peroxidation.
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