Genotoxic lipid peroxidation products: A review of their DNA-damaging properties and role in the formation of endogenous DNA adducts

The peroxidation of polyunsaturated lipids generates a range of substances that possess DNA damaging potential. This includes lipid hydroperoxides and various species that contain unpaired electrons, such as the alkoxyl and peroxyl radicals. In addition, a range of genotoxic carbonyl-containing compounds are formed, such as malondialdehyde, various 4-hydroxy-2-alkenals such as 4-hydroxynonenal and a number of 2-alkenals. It has previously been assumed that the antioxidants and electrophile scavenging enzymes existing in mammalian cells effectively protect the genetic material against these substances. However, thanks to recent analytical advances in the detection of low levels of DNA adducts, it is now evident that DNA adducts formed from a range of lipid peroxidation products are abundant in both rodent and human genomes. This suggests that the cellular defence system is not 100% efficient and that a proportion of endogenously produced lipid peroxidation products escape detoxification and cause DNA damage. This review surveys the genotoxic properties of the major classes of lipid peroxidation products, focusing on their chemistry of DNA adduction, the mutagenic properties of such damage and the evidence that it occurs in intact biological systems. Furthermore, avenues of future research that will clarify the significance of such damage to spontaneous mutagenesis and carcinogenesis are proposed and discussed.