When an antioxidant reacts with an oxidant, it is converted to a form that no longer functions as an antioxidant, and is said to be consumed. In order for the oxidized product to function again, it needs to be recycled to its native form. The antioxidant network describes the ability of the antioxidants to recycle and regenerate oxidized forms of each other thereby providing extra levels of protection (Fig. 5). Thus the process is synergistic; the net antioxidant protection is always greater than the sum of the individual effects.
The major systemic antioxidants vitamin E, vitamin C, and glutathione are present in different cellular compartments, and all have the ability to interact with one another. Typically the radicals formed on the antioxidants are more stable and longer lived than the damaging radicals produced in vivo, which is mostly attributable to delocalization of the unpaired electron. Thus they have more chance to interact with each other and be
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Figure 5 Schematics of the intertwined action of the antioxidant network. An ascorbate molecule can either recycle the vitamin E radical arising from breaking the lipid peroxidation chain, or scavenge an aqueous radical. Glutathione can either regenerate ascorbate or scavenge a radical enzymatically. Glutathione itself can then be regenerated by the cellular metabolism.
reduced than to react with macromolecules. Vitamin E is the major chain-breaking antioxidant, protecting biological membranes from lipid peroxidation , which is a difficult task considering the ratio of phospholipids molecules to vitamin E is about 1500:1. However, vitamin E is never depleted because it is constantly being recycled. When vitamin E becomes oxidized, a radical on vitamin E is formed (chromanoxyl radical). In the absence of networking antioxidants this radical can either become pro-oxidant by abstracting a hydrogen from lipids , or react to form nonradical products (consumed). However, a number of antioxidants are known to be able to reduce the chromanoxyl radical and regenerate vitamin E . These include vitamin C , ubiquinol, and glutathione (GSH) . Vitamin C, the most abundant plasma antioxidant and first line of defense, can reduce the tocopheroxyl radical, forming the ascorbyl radical. Interactions between vitamins E and C have been shown in various systems both in vivo (reviewed in Ref. 68) and in vitro  (reviewed in Ref. 70). The ascorbyl radical is practically inert and oxidizes further to form dehydroascorbic acid. This can be reduced back to native vitamin C by GSH. This process is known to occur both chemically  and enzymatically  in both erythrocytes  and neutrophils induced by bacteria ; the latter may relate to a host defense mechanism. Glutathione is the major intracellular antioxidant. Oxidized GSSG is constantly recycled to GSH enzymatically by glutathione reductase, thus providing a constant pool of GSH. Glutathione recycling relies on NAD(P)H as the electron donor. Thus metabolic pathways involved in energy production provide the ultimate electron donors for the antioxidant network. It is also known that GSH can directly recycle vitamin E [65,75], as can ubiquinol , another lipophilic antioxidant which itself is recycled in mitochondria as part of the electron transport chain.
Certain supplements are also known to contribute to the network by recycling antiox-idants. Lipoic acid is a prime example since this potent antioxidant can recycle ascorbate, GSH, and ubiquinol in vitro (reviewed in Ref. 77). Recently it has been demonstrated that flavonoids may also play a networking role since they are also able to recycle the
ascorbyl radical . Thus there exists a very organized defense system against free radical attack, which ultimately serves to protect and recycle antioxidants in various cellular compartments.
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