Antioxidant Systems

Normal biological processes that make use of oxygen inevitably lead to the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide, hydroxyl radicals, nitric oxide, and peroxynitrite. While a limited amount of ROS production can serve important cell signalling and anti-microbial functions [31], when produced in larger amounts, ROS can cause oxidant stress to the host leading to cellular and tissue injury. The mechanisms by which oxidant stress causes cellular and tissue injury include damage to genomic and mitochondrial DNA, lipid peroxidation, and protein modification [32-34]. Cell death secondary to oxidant stress can be from either necrosis or apoptosis [34], In keeping with many biological processes that have counter-acting or counter-regulatory mechanisms, all aerobic organisms have well-developed antioxidant systems to protect cells and tissues against high levels of ROS production.

Superoxide dismutases (SOD) exist in several forms including Mn-SOD, Cu/Zn-SOD, and Fe-SOD [35]. In addition, SOD exists within the cytoplasmic and mitochondrial cellular compartments and in the extracellular compartment. SOD efficiently (diffusion limited) converts two superoxide molecules to hydrogen peroxide and oxygen (Fig. 1). The importance of SOD in host defence against oxidant stress is illustrated by gene knock-out studies and by numerous studies demonstrating that genetic overexpression of SOD confers protection against oxidant stress [3639]. In addition, mutations of human SOD can cause amyotrophic lateral sclerosis [40-41].

Catalases convert hydrogen peroxide to water and oxygen (Fig. 1) [42,43]. Thus, they can operate in conjunction with SOD to defend against oxidant stress (i.e., the hydrogen peroxide formed by SOD catalysis can be converted by catalases). In addition, by lowering intracellular levels of hydrogen peroxide, catalase can prevent formation of hydroxyl radicals that could occur via the Fenton reaction (Fig. 1). Glutathione (GSH) peroxidases consist of at least four isoforms in mammals and are widely distributed [43]. Similar to catalase, all members of the GSH peroxidases can convert hydrogen peroxide to water by using glutathione as a substrate.

Haemoglobin is a known scavenger of nitric oxide in mammalian systems and given the abundance of haemoglobin in all mammals, this mechanism is likely to be a central component for mammalian detoxification of nitric oxide [44]. Gardner et al., however, have recently discovered enzymatic systems within both aerobic and anaerobic bacteria that can efficiently detoxify/ scavenge nitric oxide [45-49]. It is anticipated that homologous nitric oxide reducing systems will be described in mammalian cells in the near future [50].

Another major antioxidant mechanism in mammals is the thioredoxin system, which is composed of the oxidoreductase enzymes thioredoxin and thioredoxin reductase [51]. In conjunction with NADPH, thioredoxin reductase leads to the reduction of the active disulfide site of thioredoxin. Thioredoxin, in turn, can broadly function as a protein disulfide reductant. Another mechanism by which the thioredoxin system serves as an antioxidant is by the regeneration of various low molecular weight antioxidants such as vitamin E, vitamin C, selenium-related compounds, lipoic acid, and ubiquinones [51].

In summary, potent antioxidant systems have evolved to counter balance the normal production of ROS that occurs during many cellular processes, as well as the excessive amounts of ROS that can occur during pathological states. Despite this elegant counter-regulatory system, ROS can lead to cellular injury when either a component of the antioxidant system is defective, or when the high level production of ROS overwhelms an otherwise intact antioxidant system. Recognition of this critical balance and the mechanisms involved in defending against ROS holds tremendous potential for the design of therapeutic strategies directed toward restoring the balance between ROS production and endogenous antioxidant systems.

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