In the last decade, it has become clear that virtually all mammalian cells produce reactive oxygen species. It was generally believed that these were by-products of cellular respiration and metabolism, and that they exerted toxic effects, including DNA damage and lipid oxidation. Recent evidence has demonstrated that this concept is incorrect, and that reactive oxygen species are produced in a controlled fashion and likely have critical signaling functions. Likewise, antioxidant defenses play a crucial role in modulating the ambient steady-state levels of reactive oxygen species. Biological or pharmacological manipulation of endogenous antioxidants can have a profound effect on cellular function. Emerging evidence suggests that hydrogen peroxide (H2O2) plays a particularly important role in signal transduction. H2O2 is uncharged and is freely diffusible within and between cells. Compared with other reactive oxygen species, it is also quite stable. A major source of H2O2 is a membranebound NADH/NADPH oxidase, the activity of which is regulated by hormones, growth factors, and physical forces. The primary product of this enzyme system is superoxide (O2 J), which is rapidly dismutated to H2O2 by the superoxide dismutases. Removal of H2O2 is regulated by two important enzymes, catalase and glutathione peroxidase. Reaction products of H2O2, including lipid hydroperoxides, are also biologically active.

Given the fact that the molecule is diffusible and stable and that its production and removal are highly regulated, H2O2 is an obvious candidate as a second messenger. Indeed, many studies have demonstrated that H2O2 mediates intracellular responses to extracellular stimuli. Early work showed that both tyrosine kinases and tyrosine phosphatases were targets of exogenous H2O2, and more recently several groups have demonstrated that agonist-induced activation of these enzymes is redox sensitive. Strong evidence for an involvement of H2O2 in ERK1/2 and p38 MAPK activation by growth factors and angiotensin II has been obtained by treating cells with exogenous catalase or by stably overexpressing catalase. 1, 2 H2O2 has also been shown to mediate epidermal growth factor–induced phosphorylation of its receptor and phospholipase C, 3 platelet-derived growth factor (PDGF) stimulation of STATs, 4 activation of Akt by angiotensin II, 5 and tyrosine phosphorylation of protein kinase C. 6 Activation