Thalassaemic erythrocytes: cellular suicide arising from iron and glutathione-dependent oxidation reactions?
Both beta-thalassaemic red blood cells and normal red blood cells (RBC) artificially loaded with unpaired alpha-haemoglobin chains exhibit increased amounts of membrane-bound haem and iron. In the model beta-thalassaemic RBC the amount of free haem and iron was as much as 20 times that which could have been contributed by the entrapped alpha-haemoglobin chains alone. This excess haem/iron arises from destabilization of haemoglobin via reactions between ferric iron (Fe3+), initially contributed by the unpaired alpha chains, and cytoplasmic constituents, primarily reduced glutathione (GSH). Indeed, in the presence of Fe3+ (100 microM) addition of even small amounts of GSH (0.5 mM) to dilute RBC haemolysates (0.15 mg haemoglobin/dl) greatly accelerated methaemoglobin formation. In contrast, lysates from GSH-depleted RBC demonstrated a significantly reduced rate of iron-mediated haemoglobin oxidation which was reversible by addition of GSH. The initiation, and subsequent propagation, of Fe(3+)-mediated haemoglobin oxidation was significantly inhibited by iron chelators. Finally, Fe(3+)-driven haemoglobin oxidation was synergized by low amounts of H2O2, an oxidant spontaneously generated in thalassaemic RBC. To summarize, the release of small amounts of free iron from unpaired alpha-haemoglobin chains in the beta-thalassaemic RBC can initiate self-amplifying redox reactions which simultaneously deplete cellular reducing potential (e.g. GSH), oxidize additional haemoglobin, and accelerate the red cell destruction.
Scott
M D
MD
Department of Pathology and Laboratory Medicine, Albany Medical College, New York, USA.
Eaton
J W
JW
D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004907:Erythrocyte Deformability; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008954:Models, Biological; D010084:Oxidation-Reduction; D017086:beta-Thalassemia / Q000097:blood* / Q000378:metabolism
D006454:Hemoglobins; D006861:Hydrogen Peroxide; D005978:Glutathione