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.
Department of Pathology and Laboratory Medicine, Albany Medical College, New York, USA.
M D
MD
Scott
J W
JW
Eaton
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