Tocopherols as Antioxidants

Under normal physiological conditions, cellular systems are incessantly challenged by stressors arising from both internal and external sources. The most important potential stressors are reduced derivatives of oxygen, which are classified as reactive oxygen species (ROS), and include the superoxide anion (O2'), hydroxyl radical ( OH), and oxygen-centered radicals of organic compounds (peroxyl (ROO ) and alkoxyl (RO )) together with other nonradical reactive compounds, such as hydrogen peroxide (H2O2). In addition, reactive nitrogen species such as nitric oxide (NO ), nitrogen dioxide (NO2), per-oxynitrite (ONOO2), and hypochlorous acid are involved.

Cellular systems have evolved a powerful and complex antioxidant defence system to limit inappropriate exposure to these stressors. a-Tocopherol is quantitatively the most important chain-breaking antioxidant in plasma and biological membranes. The antioxidant activities of chain-breaking antioxi-dants are determined primarily by how rapidly they scavenge peroxyl radicals, thereby preventing the propagation of free radical reactions. When the chromanol phenolic group of a-tocopherol (TOH) encounters a ROO it forms hydroperoxide (ROOH), and in the process a tocopheroxyl radical (TO ) is formed:

The rate constant (k1) for hydrogen abstraction from a-tocopherol is 2.35 x 106M21 s2 1, which is higher than that for the other tocopherols and related phenols. Because the rate constant (k2) for the chain propagation reaction between ROO and an unsatu-rated fatty acid (RH) (ROO' + RH! ROOH) is much lower than k1, at approximately 102M_1s_1 a-tocopherol outcompetes the propagation reaction and scavenges the ROO ~104 times faster than RH reacts with ROO'. Thus, the kinetic properties of antioxidants, in particular a-tocopherol, require that only relatively small concentrations are required for them to be effective. The concentration of a-tocopherol in biological membranes is approximately 1 mol per 1000-2000 mol phospholipids (i.e., ~1:103). Ascorbic acid can reduce the toco-pheroxyl radical (TO ) to its native state, and it has been concluded that part of the reason why low concentrations of a-tocopherol are such efficient antioxidants in biological systems is because of this capacity to be regenerated by intracellular reduc-tants such as ascorbic acid.

The heteroxyclic chromanol ring of a-tocopherol has an optimised structure for resonance stabilization of the unpaired electron of the a-tocopheroxyl radical, and the electron-donating substituents (e.g., the three methyl groups) increase this effect. Because 7-tocopherol lacks one of the electron-donating methyl groups on the chromanol ring, it is somewhat less potent in donating electrons than a-toco-pherol and is thus a slightly less powerful antioxidant. However, the unsubstituted C5 position on 7-tocopherol allows it to trap lipophilic electrophiles such as peroxynitrite, thereby protecting macromolecules from oxidation.

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