4-Oxo-2-nonenal forms heptanone-etheno-2'-deoxyguanosine (dGuo), heptanone-etheno-2'-deoxyadenosine (dAdo), and heptanone-etheno-2'-deoxycytidine adducts with DNA (2,3); whereas 4,5-epoxy-2(E)-decenal forms unsubstituted etheno-dGuo and etheno-2'-dAdo adducts with DNA (2). This latter observation provides an important link between lipid peroxidation and DNA damage. Unsubstituted etheno-dAdo adducts, which are potent mutagens in mammalian cells, have been detected in human tissue DNA and urine. We made the surprising observation that vitamin C can stimulate the breakdown of lipid hydroperoxides to a,b-unsaturated aldehyde genotoxins (1). Using LC/electrospray (ESI)/MS/MS and matrix-assisted laser desorption/ionization/time of flight (MALDI/TOF)/MS and MALDI/TOF/MS/MS we have begun to systematically characterize the lesions that can also occur in proteins. Functional studies have focused on histone proteins because of the possibility that lipid hydroperoxide-mediated epigenetic effects may be induced during oxidative stress. Using a combination of deuterium isotope labeling and LC/MS/MS, it was demonstrated lipid hydroperoxides caused the formation of a cyclic peptide on the HAK motif of histone H4. Current experiments are directed at demonstrating whether this modification can occur on histone proteins during oxidative stress in vivo.
Supported by NIH RO-1 CA95586 and RO-1 CA91016.
References
1. Lee SH, Oe T, Blair IA. Science. 2001;292:2083-6.
2. Lee SH, Oe T, Blair IA. Chem Res Toxicol. 2002;15:300-4.
3. Pollack M, Oe T, Lee SH, Silva Elipe MV, Arison BH, Blair IA. Chem Res Toxicol. 2003;16:893-900.
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