Etsuo Niki University of Tokyo e-mail: eniki@Oxygen.rcast.u-tokyo.ac.jp Design and evaluation of novel antioxidant

The polyunsaturated lipids are susceptible to oxidation. Lipid peroxidation results in general in deleterious effects. Foods become rancid, while lipid peroxidation in vivo has been implicated in various diseases, cancer and aging. Accordingly, the role of antioxidants against such oxidative stress has received much attention. The mechanism and dynamics of lipid peroxidation have been studied extensively and they are now well understood. Lipids are oxidized by three mechanisms depending on the oxidants. They are (1) free radical-mediated chain oxidation, (2) non-radical, non-enzymatic oxidation, and (3) enzymatic oxidation. The free radical oxidation is often called autoxidation, which proceeds by chain mechanism, that is, one initiating radical may oxidize many molecules of lipids. The chain carrying species are the lipid peroxyl radicals which attack bisallylic hydrogens preferentially. For example, the autoxidation of linoleic acid and its esters gives mixtures of four conjugated hydroperoxides as manor primary products. The non-radical, non-enzymatic lipid peroxidation by, for example, singlet oxygen proceeds stoichiometrically, that is, one molecule of singlet oxygen oxidizes one molecule of lipids to give lipid hydroperoxide. The enzymatic oxidation in general proceeds, by regio-, stereo-, and enantio-specific mechanism. For example, 15-lipoxygenase oxidizes linoleic acid to give 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid exclusively. The lipid peroxidation in cell membranes and lipoproteins in vivo must proceed by substantially the same mechanism, though probably by different dynamics. We aerobic organisms are protected against oxidative stress by an efficient defense system. Various antioxidants with different functions play an important role in this system. Metal-sequestering proteins and peroxide-decomposing enzymes suppress the formation of free radicals and quench active oxygen species. The radical-scavenging antioxidants such as vitamin C and vitamin E scavenge active radicals before they attack substrates. Furthermore, there are such antioxidants that repair the damage, excrete toxic or waste oxidation products and reconstitute membranes. With increasing evidence which shows the deleterious effects of oxidative damage in vivo, the role of natural and synthetic antioxidants have been recognized.