The red cell has several lines of defense against oxidative stress. Hydrogen peroxide (H₂O₂: in red) at the center, is a powerful oxidizing agent arising from superoxide (O₂⁻) via superoxide dismutase (SOD). O₂⁻ (representing in this figure, in red, ROS in general) is a by-product of auto-oxidation of Hb within the red cells, and also of the oxidative burst in neutrophils (endogenous sources, in orange). In red cells, H₂O₂ can be detoxified to H₂O (in green) by 3 different enzyme-mediated mechanisms. (i) Catalase directly degrades H₂O₂ to H₂O: it has 2 to 4 molecules of NADPH in its structure.²⁵  (ii) Glutathione peroxidase (GPX) catalyzes the same reaction coupled to the oxidation of reduced glutathione (GSH): it relies on the NADPH-linked glutathione reductase (GR) for regeneration of GSH. (iii) Peroxiredoxin-2 (Prx2) also degrades H₂O₂ at the expense of its own sulhydryl groups that become disulphides, and can be regenerated by thioredoxin (Trx) through thioredoxin reductase (TrxR).²⁶  We do not know in quantitative terms the relative contributions of these 3 mechanisms to the degradation of H₂O₂ in human red cells under different conditions. However, we do know that acatalasemia is not associated with hemolytic anemia, whereas GR deficiency is associated with favism,²⁷  supporting the importance of mechanism (ii); Prx2 deficiency in humans is not known, but it does cause hemolytic anemia in mice. Most important, all 3 mechanisms depend on NADPH, a steady supply of which can be provided in red cells only by G6PD (and 6PGD, which, however, depends on G6PD for supply of its own substrate; therefore, the crucial role of G6PD is highlighted in blue). Exogenous agents (in purple) can impose severe oxidative challenge by producing ROS or H₂O₂ directly; divicine, the aglycone of vicine (together with isouramil), is the chemical responsible for favism.