GENOTOXIC LIPID-PEROXIDATION PRODUCTS - THEIR DNA-DAMAGING PROPERTIESAND ROLE IN FORMATION OF ENDOGENOUS DNA-ADDUCTS

The peroxidation of polyunsaturated lipids generates a range of substa nces that possess DNA damaging potential. This includes lipid hydroper oxides and various species that contain unpaired electrons, such as th e alkoxyl and peroxyl radicals. In addition, a range of genotoxic carb onyl-containing compounds are formed, such as malondialdehyde, various 4-hydroxy-2-alkenals such as 4-hydroxynonenal and a number of 2-alken als, It has previously been assumed that the antioxidants and electrop hile scavenging enzymes existing in mammalian cells effectively protec t the genetic material against these substances. However, thanks to re cent analytical advances in the detection of low levels of DNA adducts , it is now evident that DNA adducts formed from a range of lipid pero xidation products are abundant in both rodent and human genomes. This suggests that the cellular defence system is not 100% efficient and th at a proportion of endogenously produced lipid peroxidation products e scape detoxification and cause DNA damage. This review surveys the gen otoxic properties of the major classes of lipid peroxidation products, focusing on their chemistry of DNA adduction, the mutagenic propertie s 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 carcinogen esis are proposed and discussed.