Oxygen metabolism, although essential for life, imposes a potential threat to cells because of the formation of partially reduced oxygen species.^1,2 One electron reduction of oxygen produces superoxide whereas two electron reduction produces hydrogen peroxide. Therefore, electron flow through oxygen, utilizing processes such as the mitochondrial electron transport chain, flavoproteins, cytochrome P450 and oxidases, is tightly coupled to avoid partial reduction of oxygen.³

Normal cellular homeostasis is a delicate balance between the rate and magnitude of oxidant formation and the rate of oxidant elimination. Oxidative stress can, therefore, be defined as the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. Experimental support for oxidative stress as a mediator of cell death was provided recently by the finding that PC12 cells die following downregulation of Cu/Zn superoxide dismutase.⁴

Antioxidant defenses fall into two categories; enzymatic and nonenzymatic.^1-3 Superoxide dismutases are metalloproteins that dismutate the superoxide radical (O₂^•) to hydrogen peroxide (H₂O₂) and molecular oxygen. Three types of superoxide dismutases are found in eukaryotic cells; Cu/Zn superoxide dismutase, predominantly located in the cytosolic fractions; Mn superoxide dismutase, located in the mitochondria, and EC superoxide dismutase, which is found in the extracellular space.¹ Catalase, a heme protein located predominantly in peroxisomes and the inner mitochondrial membrane, catalyzes the conversion of H₂O₂ to H₂O. In mammalian cells, the conversion of H₂O₂ to H₂O is also accomplished by the reaction with glutathione catalyzed by glutathione peroxidases, a family of cytosolic selenoenzymes. Non-enzymatic defenses include small molecules such as membrane associated a-tocopherol, ascorbate and glutathione.

Figure 1. Antioxidant Network

Biochemistry of Reactive Species: Free Radicals vs. Oxidants
The term free radicals has been equated with reactive species or oxidants. By definition, a radical is a molecule possessing an unpaired electron. Superoxide, nitric oxide, hydroxyl, alkoxyl and alkyl-peroxyl (lipid) are radicals. However, with the exception of hydroxyl radical none of these radicals are strong oxidants. Thus, not all radicals are strong oxidants and not all oxidants are radicals.

A critical function of reactive species is immunological host response. Generation of reactive species and strong oxidants by inflammatory cells is essential for killing invading microorganisms. However, experimental evidence has implicated reactive species in the pathogenic mechanism of several diseases. It is, therefore, important to understand the biochemical pathways for the induction of oxidative stress by reactive species. The most reasonable biochemical hypothesis is the reactive species-mediated modification of critical cellular targets. Read More...