Protein Antioxidants in Thalassemia

Abstract

It is common knowledge that thalassemic patients are under significant oxidative stress. Chronic hemolysis, frequent blood transfusion, and increased intestinal absorption of iron are the main factors that result in iron overload with its subsequent pathophysiologic complications. Iron overload frequently associates with the generation of redox-reactive labile iron, which in turn promotes the production of other reactive oxygen species (ROS). If not neutralized, uncontrolled production of ROS often leads to damage of various intra- and extracellular components such as DNA, proteins, lipids, and small antioxidant molecules among others. A number of endogenous and exogenous defense mechanisms can neutralize and counteract the damaging effects of labile iron and the reactive substances associated with it. Endogenous antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and ferroxidase, may directly or sequentially terminate the activities of ROS. Nonenzymatic endogenous defense mechanisms include metal binding proteins (ceruloplasmin, haptoglobin, albumin, and others) and endogenously produced free radical scavengers (glutathione (GSH), ubiquinols, and uric acid). Exogenous agents that are known to function as antioxidants (vitamins C and E, selenium, and zinc) are mostly diet-derived. In this review, we explore recent findings related to various antioxidative mechanisms operative in thalassemic patients with special emphasis on protein antioxidants.

Introduction

Thalassemia is a group of inherited disorders characterized by the reduced or absent synthesis of one or more of the globin chains of hemoglobin (Hb). The severity and the clinical manifestations of the disease relate partly to the amount of globin chains produced and to the stability of residual chains present in excess. Reduced or absent synthesis of a particular globin chain leads to decreased synthesis of Hb and accumulation of unbound free chains. Free chain precipitation leads to ineffective erythropoiesis in erythroid precursor cells and membrane damage and hemolysis in mature red blood cells [1].

The word thalassemia is Greek for “thalassa,” which means sea. Although originally coined to refer to inhabitants of the Mediterranean region, thalassemia is now one of the most common autosomal recessive genetic disorders in almost all ethnic groups around the world [2]. β-Thalassemia is prevalent in populations of the Mediterranean, the Middle East, Central Asia, India, the Far East, Eastern Europe, and Africa. α-Thalassemia, on the other hand, is more common in Southeast Asia, India, the Middle East, and Africa [3]. Due to increased population mobility over the last 50 years, thalassemia is now considered an important health problem in all parts of the world. For example, Hb E/β-thalassemia, which is very common in the Indian subcontinent and Asia, mainly Thailand and Indonesia, is becoming a significant public health problem in Northern Europe, North and South America, the Caribbean, and Australia [4], [5]. Various forms of thalassemia have been identified, each involving reduced production of a distinct globin chain. The three most clinically significant forms are described in the following paragraphs.

α-Thalassemia: Reduced production of α globin chains results in excess production of γ globin chains in the fetus and newborn or β chains in children and adults. Total lack of α globin chain production in the fetus results in the formation of a γ tetramer (Hb Bart's) that ultimately leads to stillbirth (hydrops fetalis) [6], [7]. In children and adults, excess β chains aggregate forming highly unstable and easily oxidizable β4 tetramers (HbH) that precipitate within mature erythrocytes and erythrocyte precursors. Formation of insoluble inclusions, cell membrane damage, and ineffective erythropoiesis are typical consequences of this process [8]. It is worth noting that the degree of damage caused by excess beta globin chains on the RBC membrane in α-thalassemia is less than that in the case of excess alpha globin chains in β-thalassemia [9], [10]. In clinically symptomatic cases, the patient manifests severe anemia requiring intermittent transfusion therapy that does not generally associate with iron overload.

β-Thalassemia: It is characterized by reduced or absent production of the beta globin chain and hence, the classification into β-thalassemia minor, intermedia, or major. Total absence or reduced synthesis of beta chains results in the accumulation of alpha chains in mature RBCs and RBC precursors. As the free alpha chain is less soluble and highly unstable, it tends to readily precipitate and cause oxidative membrane damage to RBCs and immature erythrocytes in the bone marrow [11], [12], [13], [14]. Interestingly, the polychromatophilic normoblast stage in β-thalassemia is characterized by pronounced rates of apoptosis and the accumulation of damaged DNA [15], [16], [17]. Intramedullary hemolysis of defective RBCs, ineffective erythropoiesis, and increased rates of apoptosis in bone marrow, all contribute to the onset of severe anemia in patients with β-thalassemia major [17]. Because these patients require life-long blood transfusion, they are particularly prone to iron overload, which associates with significant tissue and organ damage.

E/β-thalassemia: Hb E results from a substitution (Glu → Lys) at position 26 of the β globin chain that leads to reduced synthesis of the β chain [18], [19]. As the resulting E chain has reduced affinity for the α chain, formed complexes are unstable and precipitate under different conditions [20]. Hb E/β-thalassemia, which is the most serious form of Hb E syndromes, is a condition that results from the coinheritance of a β-thalassemia minor trait from one parent and Hb E from the other. It ranges from mild to severe thalassemia of the transfusion-dependent type. The instability of Hb E, imbalance of globin chain synthesis, and levels of Hb F are among the determinants that affect the severity and clinical presentations of the disease [21]. Like other forms, ineffective erythropoiesis, apoptosis, oxidative damage, and shortened red cell life span are major features of this disorder.