Using mice deficient in glutathione peroxidase, Johnson et al reported that this enzyme plays an important role within erythrocytes in the detoxification of organic peroxides.1 The authors extended the discussion to include another family of peroxide detoxifying enzymes, the peroxiredoxins. Far from being restricted to micro-organisms, as implied by Johnson et al, peroxiredoxin family members are widely spread throughout mammalian tissues, including erythrocytes and macrophages.2,3 Erythrocyte Prx II (also known as calpromotin, torin, natural killer enhancing factor B, thiol-specific antioxidant protein, or thioredoxin peroxidase B) reduces both hydrogen peroxide and organic peroxides, protects the membrane against lipid peroxidation, and derives its reducing power from the thioredoxin/thioredoxin reductase/nicotinamide adenine dinucleotide phosphate system.3 At an estimated 14 million copies per cell, Prx II is one of the most abundant erythrocyte proteins after hemoglobin.4
In a second mouse model, the Prx II gene has been deleted.5 These mice showed marked abnormalities, such as overloading of the spleen with iron and deposition of denatured globin precipitates within their erythrocytes. These data are consistent with excessive levels of peroxide, which are known to break down hemoglobin, releasing the iron from the protein in soluble complexes that can react with peroxides to generate cascades of damaging free radicals.6 Prx II therefore appears to help protect hemoglobin from free radical damage.
Studies performed with erythrocyte ghosts have demonstrated that Prx II plays a role in stimulating potassium efflux via the Gardos channels by interacting with the cytosolic surface of the plasma membrane.4 Prx II membrane association and Gardos channel activity are markedly up-regulated within sickle dense cells.7 Sickle dense cells exhibit classic symptoms of oxidative stress, such as the increased oxidation of membrane thiols and higher concentrations of the products of lipid peroxidation.8
Paradoxically for an antioxidant enzyme, a mixture of structural9 and biochemical studies10have shown that Prx II itself can fall victim to rising levels of peroxide through the overoxidation of a catalytic cysteine residue to cysteine sulphinic acid. This overoxidation event inactivates the peroxidase activity. The molecular basis by which Prx II stimulates potassium efflux via the Gardos channels remains to be elucidated.
Red cells have multiple antioxidant defenses
This letter reviews earlier publications on peroxiredoxins in erythrocytes. The authors remark that Johnson et al (their reference 2) imply that peroxiredoxins occur only in bacteria. This is not quite correct, since Johnson et al only pointed out that peroxiredoxins were important players in bacterial metabolism, without commenting on their possible roles elsewhere. It is reasonable to suppose that peroxiredoxin protects red cells from free radicals. Thus, peroxiredoxins in red cells are likely to be important, and the final publication of the work described in the abstract of their reference 7 will be awaited with interest. If it were found that peroxiredoxins also participate in red cell antioxidant defense, this would not affect the data of Johnson et al showing that red cells detoxify organic peroxides with glutathione peroxidase. It is likely that cells will have more than one antioxidant mechanism.
