Thalassemia major patients using iron chelators showed a reduced plasma thioredoxin level and reduced thioredoxin reductase activity, despite elevated oxidative stress

Abstract In the present study, we aimed to investigate plasma levels of peroxiredoxin 2 (Prx2) and thioredoxin 1 (Trx1), and the activity of thioredoxin reductase (TrxR), in thalassemia major (TM) patients living in the Antalya region, Turkey. The patients were divided into three groups, according to chelators – the deferoxamine group (DFO, n = 20), the deferasirox group (DFX, n = 20), and the deferiprone group (DFP, n = 20), to compare any possible effect of chelators on antioxidative and oxidative stress parameters. A control group (n = 20) was selected from healthy volunteers. The activities of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and TrxR, as well as the concentrations of Prx2, Trx1, glucose-6-phosphate dehydrogenase (G-6-PD), reduced glutathione (GSH), hydrogen peroxide (H2O2), and malondialdehyde (MDA) were measured in the plasma samples of TM patients and the controls. The activity of CAT and the levels of H2O2 and MDA in the TM patients were significantly higher than those in the controls, while the levels of GPx, Trx1, TrxR, and GSH were lower. The concentrations of ferritin, GSH, H2O2, and MDA, as well as the activities of GR, CAT and TrxR, showed significant differences among the chelator groups. Although TrxR activity showed an increase in TM patients due to an elevated iron overload, both TrxR activity and Trx1 level were lower in the patient groups compared with the cases in the control group. As a result, because Trx1 level and TrxR activity were measured at a low level in the patients, increasing the levels of Trx1 and TrxR in TM patients will be a target of future treatment.

[1]  T. Zarei,et al.  Compliance and satisfaction with deferasirox (Exjade®) compared with deferoxamine in patients with transfusion-dependent beta-thalassemia , 2014, Hematology.

[2]  E. Neufeld,et al.  Relationship among chelator adherence, change in chelators, and quality of life in Thalassemia , 2014, Quality of Life Research.

[3]  T. Simmet,et al.  The thioredoxin system as a therapeutic target in human health and disease. , 2013, Antioxidants & redox signaling.

[4]  A. Pantaleo,et al.  Oxidative Stress and β-Thalassemic Erythroid Cells behind the Molecular Defect , 2013, Oxidative medicine and cellular longevity.

[5]  J. Yodoi,et al.  Extracellular thioredoxin: a therapeutic tool to combat inflammation. , 2013, Cytokine & growth factor reviews.

[6]  Mohsen Saleh Elalfy,et al.  Effect of Antioxidant Therapy on Hepatic Fibrosis and Liver Iron Concentrations in β-Thalassemia Major Patients , 2013, Hemoglobin.

[7]  Manisha N. Patel,et al.  Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells , 2012, PloS one.

[8]  D. Yoon,et al.  Peroxiredoxin II is essential for preventing hemolytic anemia from oxidative stress through maintaining hemoglobin stability. , 2012, Biochemical and biophysical research communications.

[9]  S. Greenwald,et al.  Altered Vascular Function, Arterial Stiffness, and Antioxidant Gene Responses in Pediatric Thalassemia Patients , 2012, Pediatric Cardiology.

[10]  A. Duits,et al.  N-acetylcysteine reduces oxidative stress in sickle cell patients , 2012, Annals of Hematology.

[11]  Mohsen Saleh Elalfy,et al.  Effect of Antioxidant Therapy On Hepatic Fibrosis and Liver Iron Concentrations In Beta-Thalassemia Major Patients , 2011 .

[12]  A. Iolascon,et al.  Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis , 2011, Haematologica.

[13]  A. Chakrabarti,et al.  Differential regulation of redox proteins and chaperones in HbEβ‐thalassemia erythrocyte proteome , 2010, Proteomics. Clinical applications.

[14]  E. Fibach,et al.  Effect of Iron Chelators on Labile Iron and Oxidative Status of Thalassaemic Erythroid Cells , 2009, Acta Haematologica.

[15]  J. Yodoi,et al.  Thioredoxin in human and experimental sepsis* , 2009, Critical care medicine.

[16]  M. Trujillo,et al.  The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2. , 2009, Archives of biochemistry and biophysics.

[17]  E. Fibach,et al.  The role of oxidative stress in hemolytic anemia. , 2008, Current molecular medicine.

[18]  E. Neufeld,et al.  Inflammation and oxidant-stress in β-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial , 2008, Haematologica.

[19]  D. Atlas,et al.  N-acetylcysteine amide (AD4) attenuates oxidative stress in beta-thalassemia blood cells. , 2008, Biochimica et biophysica acta.

[20]  C. Winterbourn,et al.  Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte. , 2007, Blood.

[21]  R. Naithani,et al.  Peroxidative stress and antioxidant enzymes in children with β‐thalassemia major , 2006 .

[22]  Mark A Westwood,et al.  Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. , 2006, Blood.

[23]  R. Naithani,et al.  Peroxidative stress and antioxidant enzymes in children with beta-thalassemia major. , 2006, Pediatric blood & cancer.

[24]  Y. Ho,et al.  Mice Lacking Catalase Develop Normally but Show Differential Sensitivity to Oxidant Tissue Injury* , 2004, Journal of Biological Chemistry.

[25]  A. Hoffbrand,et al.  Clinical trial of deferiprone iron chelation therapy in β‐thalassaemia/haemoglobin E patients in Thailand , 2003, British journal of haematology.

[26]  S. Kang,et al.  Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice. , 2003, Blood.

[27]  B. Pace,et al.  Effects of N‐acetylcysteine on dense cell formation in sickle cell disease , 2003, American journal of hematology.

[28]  E. Fibach,et al.  Flow cytometric measurement of reactive oxygen species production by normal and thalassaemic red blood cells , 2003, European journal of haematology.

[29]  Ü. Günay,et al.  LIPID PEROXIDATION AND ANTIOXIDANT STATUS IN ß-THALASSEMIA , 2000 .

[30]  B. Sahaf,et al.  Thioredoxin blood level increases after severe burn injury. , 2000, Antioxidants & redox signaling.

[31]  P Griffiths,et al.  Mice with a Homozygous Null Mutation for the Most Abundant Glutathione Peroxidase, Gpx1, Show Increased Susceptibility to the Oxidative Stress-inducing Agents Paraquat and Hydrogen Peroxide* , 1998, The Journal of Biological Chemistry.

[32]  W. Roos,et al.  Development of a new microparticle‐enhanced turbidimetric assay for C‐reactive protein with superior features in analytical sensitivity and dynamic range , 1998, Journal of clinical laboratory analysis.

[33]  R. Bronson,et al.  Mice Deficient in Cellular Glutathione Peroxidase Develop Normally and Show No Increased Sensitivity to Hyperoxia* , 1997, The Journal of Biological Chemistry.

[34]  J. Čermák,et al.  Solid-phase extraction in malondialdehyde analysis. , 1997, Analytical biochemistry.

[35]  L. Tesoriere,et al.  Oxidative stress and antioxidant status in beta-thalassemia major: iron overload and depletion of lipid-soluble antioxidants. , 1996, Blood.

[36]  D. Girelli,et al.  Oxidative Damage and Erythrocyte Membrane Transport Abnormalities in Thalassemias , 1994 .

[37]  D. Girelli,et al.  Oxidative damage and erythrocyte membrane transport abnormalities in thalassemias. , 1994, Blood.

[38]  B. Bacon,et al.  Hepatic injury in chronic iron overload. Role of lipid peroxidation. , 1989, Chemico-biological interactions.

[39]  M. Hørder,et al.  International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, , 1986 .

[40]  M. Hørder,et al.  International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-alanine: 2-oxoglutarate aminotransferase, EC 2 , 1986, Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie.