DNA Adducts with Lipid Peroxidation Products

Abstract

Homolytic decomposition of PUFA2-derived lipid hydroperoxides results in formation of the α,β-unsaturated aldehydic bifunctional electrophiles DDE, EDE, HNE, HPNE, MDA (shown as β-hydroxyacrolein), ONE, DODE, and 5,8-dioxo-(10E)-octenoic acid (see Fig. 1) (1–3). Intracellular formation of the bifunctional electrophiles can then result in the formation of GSH, protein, and DNA adducts (1–3, 5). The analysis of lipid hydroperoxide-derived DNA adducts can facilitate molecular epidemiology studies by providing insight into the amount of a genotoxin that has reached the DNA of the tissue under study (6, 7). DNA repair enzymes, such as those involved in base excision repair, are able to excise the DNA adducts so that they can potentially be excreted in the urine (7). This suggests that non-invasive MS-based techniques could be used to monitor urinary DNA adducts arising from lipid hydroperoxide-mediated DNA damage. Unfortunately, to date, the analysis of urinary DNA adducts of lipid hydroperoxide-derived bifunctional electrophiles has not been particularly successful. ONE-derived DNA adducts, which can arise only from lipid peroxidation, have now been characterized in the tissues of mouse models (8). Therefore, it might eventually be possible to detect these specific lipid hydroperoxide-derived DNA adducts after they have been excised from the DNA and excreted in the urine (see Fig. 2). FIGURE 1. Structures of lipid hydroperoxide-derived bifunctional electrophiles. FIGURE 2. Formation of eDNA and HeDNA adducts through homolytic decomposition of lipid hydroperoxides. BER, base excision repair.