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Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia.

ABSTRACT: Chronic redox imbalance in erythrocytes of individuals with sickle cell disease (SCD) contributes to oxidative stress and likely underlies common etiologies of hemolysis. We measured the amounts of six antioxidant enzymes-SOD1, catalase, glutathione peroxidase 1 (GPx1), as well as peroxiredoxins (Prxs) I, II, and VI-in red blood cells (RBCs) of SCD patients and control subjects. The amounts of SOD1 and Prx VI were reduced by about 17% and 20%, respectively, in SCD RBCs compared with control cells. The amounts of Prx II and GPx1 did not differ between SCD and normal RBCs. However, about 18% of Prx II was inactivated in SCD RBCs as a result of oxidation to sulfinic Prx II, whereas inactive Prx II was virtually undetectable in control cells. Furthermore, GPx1 activity was reduced by about 33% in SCD RBCs, and the loss of activity was correlated with hemolysis in SCD patients. RBCs from SCD patients taking hydroxyurea demonstrated 90% higher GPx1 activity than did those from untreated SCD patients, with no differences seen for the other catalytic antioxidants. Hydroxyurea induced GPx1 expression in multiple cultured cell lines in a manner dependent on both p53 and NO-cGMP signaling pathways. GPx1 expression represents a previously unrecognized potential benefit of hydroxyurea treatment in SCD patients.

SUBMITTER: Cho CS

PROVIDER: S-EPMC2935334 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia.

Cho Chun-Seok CS Kato Gregory J GJ Yang Seung Ha SH Bae Sung Won SW Lee Jong Seo JS Gladwin Mark T MT Rhee Sue Goo SG

Antioxidants & redox signaling 20100701 1

Chronic redox imbalance in erythrocytes of individuals with sickle cell disease (SCD) contributes to oxidative stress and likely underlies common etiologies of hemolysis. We measured the amounts of six antioxidant enzymes-SOD1, catalase, glutathione peroxidase 1 (GPx1), as well as peroxiredoxins (Prxs) I, II, and VI-in red blood cells (RBCs) of SCD patients and control subjects. The amounts of SOD1 and Prx VI were reduced by about 17% and 20%, respectively, in SCD RBCs compared with control cell ...[more]

PMID: 19951064

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Project description:BackgroundHydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.MethodsWe enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell-related events, transfusions, and survival).ResultsA total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).ConclusionsHydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731 .).

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Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia.

Publications

Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia.

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