PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC-ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA-DAMAGE AND CYTOGENETIC EFFECTS

In the present study, the possible role of the polyunsaturated fatty a cids linoleic and arachidonic acid in the chemical induction of carcin ogenesis has been investigated. Analysis of 7,8-dihydro-8-oxo-2'-deoxy guanosine (8-oxodG) levels in 2'-deoxyguanosine (dG) and isolated DNA has demonstrated that linoleic and arachidonic acid are capable of ind ucing this specific genotoxic damage. This effect appears to be relate d to the degree of fatty acid unsaturation, since it was not induced b y monounsaturated oleic acid. Enzymatic peroxidation of linoleic and a rachidonic acid resulted in a significant increase in oxidative DNA da mage. Studies on the interference of radical scavengers with the induc tion of 8-oxodG in combination with electron spin resonance spectrosco py demonstrated that the superoxide anion was generated during peroxid ation of these fatty acids and that singlet oxygen is most likely invo lved in the formation of oxidative DNA damage. The level of oxidative damage in dG and single-stranded DNA was higher as compared to that in native DNA after equimolar treatment. Exposure of human lymphocytes t o linoleic or arachidonic acid did not result in a significant increas e in levels of 8-oxodG. This may indicate that the rate of intracellul ar peroxidation is relatively low and/or that nuclear DNA in intact ce lls is effectively protected against genetic damage induced by reactiv e oxygen species. It is therefore concluded that relatively short peri ods of linoleic or arachidonic acid administration are not likely to i mpose a direct genotoxic risk. It can, however, not be excluded that c hronic exposure to polyunsaturated fatty acids induces oxidative DNA d amage or is related to cancer risk by epigenetic mechanisms, as is als o indicated by the observed cytotoxic effects of linoleic and arachido nic acid.