Antioxidants

ldloxldsReaction of antioxidant compounds with oxyradical species

Reactive oxygen species (ROS) are represented by activated forms of oxygen (oxyradicals or monovalent reduction products of oxygen) and organic radicals and peroxides that are produced by reaction with (O2-., superoxide radical; .OH, hydroxyl radical) and ROS (H2O2). These ROS can oxidize cell proteins (particularly sulfhydryl-rich proteins) leading to inactivation. They also readily react with and oxidize unsaturated lipids. This process is facilitated by transition metals such as iron and copper, or by heme proteins where the metal in these heme proteins are oxidized to hypervalent states that readily attack unsaturated lipids. The steps involved in the oxidation of a typical unsaturated fatty acid, linoleic acid follow: The first product is a lipid peroxyl radical, derived from oxygen addition to the lipid alkyl radical intermediate which arises by reaction of the lipid with the ROS or hypervalent metal. The peroxyl radical rapidly reacts with another lipid to generate a new peroxyl radical and a lipid hydroperoxide. This reaction proceeds at a rate constant of 106 moles/sec and represents the kinetic stages for the propagation of lipid peroxidation. By these reactions lipid hydroperoxides accumulate, leading to the deterioration of the lipid and formation of organic ROS that account for many of the biological effects noted above.

Inhibition of lipid peroxidation by specific antioxidants: the special role of natural tocopherols and selenium

It is at this stage that tocopherols (vitamin E compounds) and related antioxidants exert an inhibitory effect. By reacting with the lipid peroxyl radical at a rate constant faster than reactions of lipid peroxyl radical with other lipids (ie. 109 moles/sec) RRR-alpha-tocopherol has a strong kinetic advantage in suppressing the propagation of lipid peroxidation. Moreover, the limited formation of hydroperoxides by reaction with vitamin E is readily managed by reactions with peroxidases, key among which are the selenium containing glutathione peroxidases which convert the potentially reactive lipid hydroperoxides to nonreactive lipid alcohols.

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How antioxidants inhibit low density lipoprotein oxidation

lagphsesReaction with vitamin E produces a relatively nonreactive vitamin E radical (vitamin E.) which can be rapidly reduced back to active vitamin E. A number of cellular reducing agents are capable of doing this, including vitamin C, lipoic acid and glutathione. The antioxidant effect of vitamin E is readily demonstrated by comparing the rates of LDL oxidation as induced by copper (although similar effects are noted when other ROS are used. The rates of peroxide formation in LDL are considerably retarded in LDL obtained from vitamin E sufficient subjects as compared to LDL from vitamin E deficient subjects. The kinetics of LDL oxidation can also be monitored spectrophotometrically. The stages of LDL lipid peroxidation can be compared for LDL from vitamin E supplemented subjects as compared to LDL from subjects normal levels of vitamin (unsupplemented). Features of the oxidation stages include: a prolonged lag period where the LDL is protected by the antioxidant and little accumulation lipid peroxidation products takes place. After vitamin E has been consumed, the lag phase ends and is followed by the propagation phase for lipid peroxidation. At this stage there may be a small decrease in the rate of reaction for vitamin E supplemented LDL, however, the important effect is to suppress peroxidation and oxidative modification of LDL in the presence of an oxidative challenge.

Examples of inhibition of oxidant-induced responses by antioxidants

ldloxldsThe reduction of the vitamin E radical by vitamin C has been well studied. This process appears to occur in tissues, and is relevant to the preservation of vitamin E in LDL. LDL can be protected from oxidation and the propagation of lipid peroxidation from one LDL particle to another is inhibited as long as sufficient amounts of vitamin E remain among the LDL lipids. In the presence of vitamin C (ascorbic acid) the consumption of vitamin E is prevented as the vitamin E radical is reduced back to vitamin E. The LDL thus does not undergo peroxidation and oxidative modification. In the absence of vitamin C, the LDL vitamin E is consumed and the vitamin E radical decomposes to an inactive product (vitamin E quinone). The LDL is no longer protected against oxidation reactions and lipid peroxidation propagates within and among vitamin E depleted particles resulting in extensive oxidative modification. Thus, a synergy exists between vitamin C and vitamin E which enhances the antioxidant properties of LDL.

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