Fig. 1—
Summary of the production of reactive oxygen species (ROS, namely, the superoxide anion radical (O2·-), hydrogen peroxide (H2O2), hydroxyl radical (·OH), singlet oxygen (1O2) and hypochlorous acid (HOCl)) and reactive nitrogen species (RNS, namely, nitric oxide (NO) and the peroxynitrite anion (ONOO-)). The most reactive of these products and, therefore, the most damaging are the ·OH and ONOO-. Since they are not enzymatically removed from the cell, the antioxidative defense system can only prevent the damage they do by scavenging them. These reactants are especially abundantly produced in mitochondria where molecular oxygen (O2) is reduced to O2·- by electrons that escape from the respiratory chain, especially at mitochondrial complexes I and III. There are a number of antioxidative enzymes that convert reactive species to less reactive products. For example, O2·- is dismutated to H2O2 by the cytosolic and mitochondrial superoxide dismutases (CuZnSOD and MnSOD, respectively). Also, H2O2 is converted to innocuous products by glutathione peroxidase (GPx) which results in the oxidation of glutathione (GSH) to form glutathione disulfide (GSSG); this latter molecule is recycled back to GSH by glutathione reductase (GRd). Intracellular GSH levels are maintained by the rate-limiting enzyme in GSH synthesis, glutamylcysteine ligase (GCL). Catalase (CAT), another antioxidative enzyme, also removes H2O2 from cells. In the presence of myloperoxidase (MPO) in leukocytes, H2O2 is converted to HOCl and H2O. The conversion of H2O2 to the highly toxic ·OH in the presence of a transition metal, usually Fe2+, is referred to as the Fenton reaction. The arrows in parenthesis after the enzymes indicate that melatonin (a recently discovered antioxidant) either stimulates (↑) or inhibits (↓) their activity. Melatonin has been shown to reduce the toxicity of ROS/RNS in human newborns. Additionally, melatonin scavenges the most toxic reactants, namely, the ·OH and ONOO- which cannot be enzymatically removed. Nitric oxide synthase (NOS) is often considered a pro-oxidative enzyme and is inhibited by melatonin.