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Antioxidants, nature and chemistry

Submitted by Dr. Tamer Fouad, M.D.

Antioxidant System

The body has developed several endogenous antioxidant systems to deal with the production of ROI. These systems can be divided into enzymatic and nonenzymatic groups. Figure 4 summarizes the sites of action of the various antioxidants.

Fig. 4: Generation sequence of reactive oxygen species following univalent reduction of oxygen and the various sites of action of the different antioxidants (Nohl, 1993).

The enzymatic antioxidants include superoxide dismutase (SOD), which catalyses the conversion of O2?to H2O2 and H2O; catalase, which then converts H2O2 to H2O and O2; and glutathione peroxidase, which reduces H2O2 to H2O.

Fig. 5: Sources of intracellular oxidative stress and sites of antioxidant activity (Bulger and Helton, 1998).

The nonenzymatic antioxidants include the lipid-soluble vitamins, vitamin E and vitamin A or provitamin A (beta-carotene), and the water-soluble vitamin C and GSH. Vitamin E has been described as the major chain-breaking antioxidant in humans (Packer, 1992). Because of its lipid solubility, vitamin E is located within cell membranes, where it interrupts lipid peroxidation and may play a role in modulating intracellular signalling pathways that rely on ROI (Kagan et al. 1990; Azzi et al. 1993). Vitamin E can also directly quench ROI, including O2?, ?OH, and (Algayer et al. 1992) 1O2.

The enzymatic and nonenzymatic antioxidant systems are intimately linked to one another and appear to interact with one another (Fig.6). Both vitamin C and GSH have been implicated in the recycling of alpha-tocopherol radicals (Reed, 1993). In addition, the trace elements selenium, manganese, copper, and zinc also play important roles as nutritional antioxidant cofactors. Selenium is a cofactor for the enzyme glutathione peroxidase, and manganese, copper, and zinc are cofactors for SOD (see earlier). Zinc also acts to stabilize the cellular metallothionein pool, which has direct free radical quenching ability (Bray and Bettger, 1990). The complex interactions of these different antioxidant systems may imply that therapeutic strategies will depend on combination therapy of various antioxidants rather than a single agent.

Fig. 6: Interactions among antioxidants. Reactive oxygen intermediates (ROI) induce membrane lipid peroxidation resulting in a chain reaction that can be interrupted by the direct scavenging of lipid peroxyl radicals by vitamin E (VE) and beta-carotene. Vitamin E can then be recycled by both vitamin C (VC) and glutathione (GSH). The reducing ability of GSH is catalyzed by the enzyme glutathione peroxidase (GSSG). Glutathione is then recycled by NADPH, which is facilitated by glutathione reductase (GSSG). LOO? = active species of the lipid peroxyradical; LOOH-reduced lipid radical; VE-O? = active radical form of VE; VE-OH = the reduced form (Bulger and Helton, 1998).

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