Lipid membrane peroxidation in beta-thalassemia major

Ea, Rachmilewitz; Shohet, SB; Lubin, BH

doi:10.1182/blood.v47.3.495.bloodjournal473495

Cited by 22 publications

(25 citation statements)

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“…PME failed to restore normal kinetics in patients, practically ruling out abnormal disulfide bonding as the sole chemical change. Unlike previous studies [24], the thalassemic patients presented in this work displayed normal fatty acid composition of the three major phosphoglyceride classes of their red cell membrane (unpublished). This makes unlikely the spontaneous production in vivo of large amounts of malonyldialdehyde, and the subsequent generation of protein cross links through Schiff base formation [25].…”

Section: Discussioncontrasting

confidence: 73%

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Kinetic alterations of the red cell membrane phosphatase in α‐ and β‐Thalassemia

et al. 1982

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We studied the red cell membrane neutral phosphatase, which is part of the Na+K+ ATPase, in several types of oxidative hemolytic anemias. We used an artificial substrate, the p-nitrophenylphosphate. In controls and in patients heterozygous for various unstable hemoglobins (Hb Hope, Hb Köln, or Hb Hammersmith), the kinetics were of the Michaelis-Menten type. On the contrary, in nearly all patients with alpha- or beta-thalassemia, the kinetics displayed an abnormally biphasic character. The apparent Michaelis constant (KMapp) was significantly decreased. The biphasic character correlated with the imbalance of globin chain synthesis. The beta-mercaptoethanol markedly increased Vmax in controls, but had little effect on the biphasic kinetics. Omission of K+ abolished the biphasic kinetics. The abnormal kinetics failed to appear with another artificial substrate, the 4-methylumbelliferylphosphate, nor did it appear with ATP, the natural substrate. In vitro, H2O2 treatment of normal and thalassemic red cells was unable to induce or exaggerate, respectively, the biphasic kinetics, but generated alterations of a different nature. We suggest that the various kinetic alterations of the phosphatase in thalassemic syndromes originate from the imbalance of globin chain synthesis. However, the involvement of an oxidative process remains to be demonstrated.

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Section: Discussioncontrasting

confidence: 73%

“…MDA formation was 262 and 625 nmollg Hbl2 hours. respectively, a fact confirming the increased susceptibility of thalassemic red cells to oxidant stress [24]. After ghost preparation, phosphatase was assayed in the absence (--) or in the presence (---) of PME (150 mM).…”

Section: Discussionmentioning

confidence: 88%

Kinetic alterations of the red cell membrane phosphatase in α‐ and β‐Thalassemia

et al. 1982

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“…Moreover, in vivo RBV treatment determined an increase in methemoglobin level, as well as in malondialdehyde (MDA) erythrocyte content, which is known to be a typical product of oxidative damage (Table 5). 37,38 In the present article we provide evidence for significant alterations of the erythrocyte membrane induced by RBV therapy, which are known to be associated with erythrophagocytic extravascular destruction. The signal for erythrocyte recognition and removal by phagocytes seemed to reside in the large amount of deposited autologous IgGs and C3 complement fragments, both secondary to band 3 aggrega-tion, observed in all patients ( Figs.…”

Section: Discussionmentioning

confidence: 72%

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

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“…Microcytosis is the physiopathologcal consequence of reduced red blood cell (RBC) haemoglobin content due to a defect in the synthesis either of globin chains or of the haem group. In addition to the morphologic, biochemical and metabolic changes, microcytic RBCs are characterized by a shorter survival (4,5 ) the oxidative damage of RBC membrane being one of the underlying mechanism (6,7). Experimental result from different mechanisms operating together: intracellular excess of unpaired globin chains, high intracellular content of nonhaemoglobin iron or from low concentration of normal haemoglobin (8,9).…”

Section: Introductionmentioning

confidence: 99%

Increased susceptibility of microcytic red blood cells to in vitro oxidative stress

Corrons

Miguel-García

Pujades

et al. 1995

European J of Haematology

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Oxidative damage to erythrocytes in thalassaemia has been related to generation of free radicals by an excess of denaturated α‐ or β‐globin chains, intracellular iron overload and low concentration of normal haemoglobin (HGB). Two good indicators of such oxidative damage are the high red blood cell (RBC) malonyldialdehyde (MDA) production detected following exogenous oxidant stress and the decrease of pyrimidine 5′‐nucleotidase (P5N), the most sensitive enzyme to SH‐group damage in vivo. Conflicting data, however, have so far accumulated in the literature concerning differences in oxidative damage between the different forms of thalassaemia and iron deficiency anaemia (IDA). In the present study, oxidative susceptibility, as defined by the production of MDA in vitro and antioxidant capacity, as measured by the activity of RBC glutathione peroxidase (GPx), superoxide dismutase (SOD) and by reduced glutathione (GSH), have been studied in microcytic RBCs from patients with β‐thalassaemia trait, Spanish (δβ)°‐thalassaemia heterozygotes (δβ‐thalassaemia trait) and iron deficiency anaemia (IDA). The results are consistent with the existence of significant differences in the severity and pattern of oxidative stress susceptibility between β‐thalassaemia trait (increased MDA production and higher SOD and GPx activities) and the other two forms of microcytosis (δβ thalassaemia trait and IDA). Furthermore, the finding of normal P5′N activity in δβ thalassaemia trait, gives further support to the less intense peroxidative environment of RBCs in this form of thalassaemia when compared to β‐thalassaemia trait, characterized by acquired RBC P5′N deficiency due to oxidative damage.

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Lipid membrane peroxidation in beta-thalassemia major

Cited by 22 publications

References 0 publications

Kinetic alterations of the red cell membrane phosphatase in α‐ and β‐Thalassemia

Kinetic alterations of the red cell membrane phosphatase in α‐ and β‐Thalassemia

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Increased susceptibility of microcytic red blood cells to in vitro oxidative stress

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