No abstract

Peroxiredoxin-2 (Prdx2), a potent peroxide reductant, is the third most abundant protein in the erythrocyte and might be expected to play a major role in the cell's oxidative defenses. However, in this study, experiments with erythrocytes from mice with a disrupted Prdx2 gene found that the cells were not more sensitive to exogenous H 2 O 2 or organic peroxides than wild-type. Intraerythrocytic H 2 O 2 was increased, however, indicating an important role for Prdx2 in detoxifying endogenouslygenerated H2O2. These results are consistent with proposals that red cell Prdx2 acts stoichiometrically, not catalytically, in reducing peroxides. Additional experiments with mice with disrupted catalase or glutathione peroxidase (Gpx1) genes showed that Gpx1 is the only erythrocyte enzyme that reduces organic peroxides. Catalase(−/−) cells were readily oxidized by exogenous H 2 O 2 . Cells lacking both catalase and Gpx1 were more sensitive to exogenous H 2 O 2 than cells lacking only catalase. A kinetic model proposed earlier to rationalize results with Gpx1(−/−) erythrocytes also fit the data with Prdx2(−/−) cells, and indicates that while Gpx1 and Prdx2 both participate in removing endogenous H 2 O 2 , Prdx2 plays a larger role. Although the rate of H 2 O 2 production in the red cell is quite low, Prdx2-deficient mice are anemic, suggesting an important role in erythropoiesis.

A1298C polymorphisms is associated with an increased risk for ALL in Filipino children. This may be due to a difference in leukemia biology or to a high prevalence of folate deficiency in Filipinos. Our study reiterates the gene and environment interaction in leukemogenesis.

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Chronic nonspherocytic hemolytic anemia has been observed in a recently described glucose-6-phosphate dehydrogenase (G6PD) variant, G6PDWayne. The mechanical properties of these erythrocytes and other G6PD variants were examined. The deformability of G6PD-deficient erythrocytes was normal, as determined by osmotic scan ektacytometry, and was not significantly affected by hemolytic crisis. In the common varieties of G6PD deficiency, the mechanical stability of the red blood cell (RBC) membrane was greater than normal, but G6PDWayne membranes were abnormally susceptible to shear-induced fragmentation. There was no evidence for a concurrent genetic defect in spectrin, because self- association constants and tryptic digests were normal. The fragility of G6PDWayne membranes appeared to be a consequence of oxidative damage to membrane thiol groups associated with a low glutathione (GSH) level in these RBCs. Associations among GSH level, thiol oxidation, and membrane instability were also found when a larger group of G6PD-deficient RBCs were examined. In normal erythrocytes, 1-chloro-2,4-dinitrobenzene was used to reduce GSH levels by 50%. Membrane thiol oxidation and membrane fragility both increased when these cells were kept at 4 degrees C for 3 to 5 days. Our findings suggest that chronic depletion of GSH leads to the destabilization of membrane skeleton through oxidation of membrane protein thiols.

malignancy at 5 years was 0.43 (95% CI 016-1.15) and was unchanged at 10 years.Our data allow some interesting considerations. The probability of developing an acute leukemia in patients who received chemotherapy or radiotherapy for a previous malignancy (PM), including acute leukemia, is a well-known occurrence: secondary forms constitute approximately 8% to 10% of all acute leukemias and are usually myeloid. 6 The main reason for this event is that several drugs employed in the treatment of the PM, particularly topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines), and combined chemotherapy including alkylating agents, are considered potentially mutagenic. As suggested by Latagliata et al, 1 the use of intensive chemotherapy to cure APL, with the inclusion of topoisomerase II inhibitors, has a potential role in inducing a tMDS-AML. 7 In our cohort of patients, the number of secondary malignancies is lower than expected in the normal population. The estimated cumulative incidence at 5 and 10 years is also lower than that expected. Furthermore, the brief latency between the onset of the 2 malignancies leads to the hypothesis that the second malignancy is probably not related to the carcinogenic action of the drugs employed for the treatment of APL, but perhaps to a chance association only.These considerations suggest that APL treatment is not relevant in inducing the onset of secondary nonhematological malignancies. On the contrary, the action of topoisomerase II inhibitors, which represent one of the main anticancer drugs used in APL, could favor the development of a tMDS-AML with a leukemogenic action on blood stem cells.

No abstract

The role of glutathione peroxidase in red cell anti-oxidant defense was examined using erythrocytes from mice with a genetically engineered disruption of the glutathione peroxidase-1 (GSHPx-1) gene. Because GSHPx-1 is the sole glutathione peroxidase in the erythrocyte, all red cell GSH peroxidase activity was eliminated. Oxidation of hemoglobin and membrane lipids, using the cis-parinaric acid assay, was determined during oxidant challenge from cumene hydroperoxide and H2O2. No difference was detected between wild-type red cells and GSHPx-1–deficient cells, even at high H2O2 exposures. Thus, GSHPx-1 appears to play little or no role in the defense of the erythrocyte against exposure to peroxide. Simultaneous exposure to an H2O2 flux and the catalase inhibitor 3-amino-1,2,4-triazole supported this conclusion. Hemoglobin oxidation occurred only when catalase was depleted. Circulating erythrocytes from the GSHPx-1–deficient mice exhibited a slight reduction in membrane thiols, indicating that high exposure to peroxides might occur naturally in the circulation.