Etheno lipid peroxidation

Figure 22.7. The major DNA lesions of the lipid peroxidation products. (A) DNA lesions produced by malondialdehyde. Mi denotes the monomeric form of malondialdehyde. Malo-ndialdehyde can polymerize to form dimers and trimers that can also react with DNA. The resulting lesions are designated as M2 and M3, respectively (c.g., M2G). These lesions, however, may not be significant in cells as polymerization of malondialdehyde is relatively slow at neutral pH. (B) The l,7V2-propano-dG DNA adducts produced by acrolein, crotonaldehyde, and 4-hydroxy-2-nonenal (HNE). Stereochemistry is not shown. The l.A -acrolcin-dG consists of three isomers. The 1, AAcrotonaldchyde-dG consists of two isomers. The FAAlINF-dGconsistsof four isomers. (C)EthenoDNAadductsproduced by 2,3-epoxy-4-hydroxynonenal. Further oxidation of 4-hydroxynonenal produces 2,3-epoxy-4-hydroxynonenal, which reacts with DNA to form the exocyclic etheno adducts.

In a similar biochemically oriented vein, several papers were published during 2003 in the journal Chemical Research in Toxicology, representing yet another area of applicability of 3 mm NMR probe capabilities. In the first of these reports, Hankin et al.159 described the results of an investigation into the covalent binding of leukotriene A4 to DNA and RNA. Later in 2003, Blair and co-workers160 reported on the characterization of 2 -deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Two of the adducts characterized, Ai and A2, were consistent with substituted ethano-deoxycytidine structures. The third adduct, B, was characterized as a 7-heptanone-etheno-deoxycytidine adduct (78). 

The major aldehyde products of lipid peroxidation are malon-dialdehyde and 4-hydroxynonenal (Table 1, Fig. 4). Malondi-aldehyde can react with DNA to generate adducts at the bases A, C, and G. The mutagenic adduct MIG (pyrimido(l,2-a)purin-10(3H)one) has been detected at levels as high as 1 adduct per 10 nucleosides in human tissues. MIG is a reactive electrophile that can undergo further modification, leading to crosslinking of an adducted DNA strand to the opposite strand, or to some protein (22). Exocyclic etheno adducts can also arise from lipid peroxidation, possibly by reaction of an epoxide of 4-hydroxynonenal with A, C, or G in DNA. 

Figure 2.8 Lipid peroxidation-derived etheno adducts.

Nair, J., De Flora, S., Izzotti, A., and Bartsch, H. (2007) lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions. Mutat. Res., 621, 95-105. 

Lee and Blair provided a critical link from lipid peroxidation to the formation of etheno adducts by demonstrating the reactivity of 4-hydroperoxy-2-nonenal, 4-oxo-2-nonenal, and 4,5-epoxy-2-decenal with nucleosides. Both 4-hydroperoxy-... 

The third type of oxidative damage that can occur in DNA would result from the addition of bifunctional electrophiles (4-hydroxy-2-nonenal and 4-oxo-2-none-nal) that result from lipid peroxidation to the nucleobases. The etheno adducts formed with 4-hydroxy-2-nonenal can also be derived from vinyl chloride however, the heptano-etheno adducts derived from 4-oxo-2-nonenal can only be derived from lipid peroxidation [115], Thus far no attempt has been made to measure these adducts as a result of the AKR pathway of PAH activation. 

It is important to note that the modifications generated by those lipid oxidation products contribute nearly to the same extent to DNA damage than the direct oxidized bases (Winczura et al. 2012). These lipid peroxidation aldehydes-DNA adducts have been reported in vivo in rodent and human DNA, in a wide variety of organs and tissue. For most of them, they can be found at a basal state (Marnett 1999 Nair et al. 1999, 2007), but their concentration is increased in the case of oxidative stress due, for instance, to inflammatory processes (Nair et al. 2007), but also in the case of PUFA-rich diet (Fang et al. 2007). For etheno-adducts, most of the studies report the presence of unsubstituted adducts, making the identification of the reactant enal impossible. However, a substituted etheno-adduct specific to the lipid oxidation product 4-oxo-nonenal has been found in greater amounts in the small intestine of mice prone to intestinal cancer (Min mice) and overexpressing the enzyme COX-2 involved in inflammatory processes than in the small intestine of control mice (Williams et al. 2006). 

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