THALASSEMIC 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 i ncreased amounts of membrane-bound haem and iron. In the model beta-th alassaemic RBC the amount of free haem and iron was as much as 20 time s that which could have been contributed by the entrapped alpha-haemog lobin chains alone, This excess haem/iron arises from destabilization of haemoglobin via reactions between ferric iron (Fe3+), initially con tributed by the unpaired ct chains, and cytoplasmic constituents, prim arily reduced glutathione (GSH), Indeed, in the presence of Fe3+ (100 mu M) addition of even small amounts of GSH (0.5 nm) to dilute RBC hae molysates (0.15 mg haemoglobin/dl) greatly accelerated methaemoglobin formation, In contrast, lysates from GSH-depleted RBC demonstrated a s ignificantly reduced rate of iron-mediated haemoglobin oxidation which was reversible by addition of GSH, The initiation, and subsequent pro pagation, of Fe3+-mediated haemoglobin oxidation was significantly inh ibited by iron chelators. Finally, Fe3+-driven haemoglobin oxidation w as synergized by low amounts of H2O2, an oxidant spontaneously generat ed in thalassaemic RBC. To summarize, the release of small amounts of free iron from unpaired alpha-haemoglobin chains in the beta-thalassae mic RBC can initiate self-amplifying redox reactions which simultaneou sly deplete cellular reducing potential (e.g. GSH), oxidize additional haemoglobin, and accelerate the red cell destruction.