Intake of n-3 Polyunsaturated Fatty Acids and In Vivo Lipid Peroxidation

The preventive effects of n-3 polyunsaturated fatty acids (PUFAs) on cardiovascular diseases are well acknowledged. In particular, docosahexaenoic acid (DHA) is the predominant n-3 PUFA with distinctive physiological functions. Recently, the anti-inflammatory action of DHA in relation to its inhibitory effects on atherosclerosis has come under intense scrutiny. However, n-3 PUFAs are very prone to lipid peroxidation because of their unstable chemical structures, and thus there is a concern that a high level of DHA intake might enhance susceptibility to in vivo lipid peroxidation. Focusing on the most highly unsaturated DHA, we have undertaken studies using rats as a model animal, in order to test a hypothesis that there are primarily two suppressive mechanisms acting against PUFA-induced lipid peroxidation in the healthy body; one is an antioxidative mechanism that suppresses the generation of lipid peroxides, and the other is a detoxification and/or excretion mechanism. We then found that tissue lipid peroxides increased in a DHA dose-dependent manner, but reached a plateau and did not increase to the extent calculated using the peroxidizability index (a parameter that indicates the relative rate of peroxidation). In addition, even with a high dose of DHA, neither the end products of lipid peroxidation (e.g. lipofuscin) nor tissue injuries were observed. We therefore confirmed that the above hypothesis was feasible, and carried out further investigations. We have so far revealed the following antioxidative mechanisms; 1) the uptake of DHA differs among tissues, and the unsaturation level of membrane fatty acids is important for production of lipid peroxides; 2) the uptake of DHA into phospholipid species differs among tissues, and resistance to peroxidation increases when DHA is incorporated into phosphatidylethanolamine; 3) a high level of DHA intake transiently increases the uptake of DHA into tissue triglyceride, by which DHA can be protected from peroxidation; 4) induction of antioxidative enzymes is not observed; 5) DHA intake increases the generation of ascorbic acid (AsA) and glutathione (GSH), which also increases the antioxidative potency of VE; and 6) it is impossible to suppress lipid peroxidation completely even with high doses of VE, AsA and GSH. We have previously observed that lipid peroxidation-derived degradation products, particularly reactive aldehydic compounds, do not form a Schiff base upon reaction with macromol ecules, and therefore the end products of lipid peroxidation (e.g. lipofuscin) are not detected. Our studies of the detoxification and/or excretion mechanisms of aldehydic compounds have indicated the following possible pathway: The aldehydic compounds produced after a high level of DHA intake form conjugates with GSH through catalysis by glutathione S-transferases in the liver, are transferred to the kidney through the bloodstream, metabolized and converted to mercapturic acids, and eventually excreted in to urine. The process of excretion of these conjugates in the liver may be mediated by MRP3 (ABCC3), one of the members of the ABC transporter family. Besides, aldose reductase and aldehyde dehydrogenases may be involved in the metabolism of aldehydic compounds. Further studies are necessary to verify the precise mechanisms involved. It is very important to reveal the dynamics of lipid peroxidation induced by PUFAs in order that they can be utilized effectively. We believe that our findings indicate the presence of some novel detoxication and/or excretion mechanisms.