Metal-catalyzed oxidation of 2-alkenals generates genotoxic 4-oxo-2-alkenals during lipid peroxidation

Abstract

<p>Lipid peroxidation products react with cellular molecules, such as DNA bases, to form covalent adducts, which are associated with aging and disease processes. Since lipid peroxidation is a complex process and occurs in multiple stages, there might be yet unknown reaction pathways. Here, we analyzed comprehensively 2′-deoxyguanosine (dG) adducts with oxidized arachidonic acid using liquid chromatography–tandem mass spectrometry and found the formation of 7-(2-oxo-hexyl)-etheno-dG as one of the major unidentified adducts. The formation of this adduct was reproduced in the reaction of dG with 2-octenal and predominantly with 4-oxo-2-octenal (OOE). We also found that other 2-alkenals (with five or more carbons) generate corresponding 4-oxo-2-alkenal-type adducts. Importantly, it was found that transition metals enhanced the oxidation of C4-position of 2-octenal, leading to the formation of OOE-dG adduct. These findings demonstrated a new pathway for the formation of 4-oxo-2-alkenals during lipid peroxidation and might provide a mechanism for metal-catalyzed genotoxicity.</p> <p>4-Oxo-2-alkenals, which are highly reactive to nucleosides, are generated through metal-catalyzed oxidation of corresponding 2-alkenals during lipid peroxidation.</p