PHARMACOLOGICAL INTERCEPTION OF HEME - A POTENTIAL THERAPEUTIC STRATEGY FOR THE TREATMENT OF BETA-THALASSEMIA

Pro-oxidant effects of hemoglobin-derived heme and iron contribute to the progressive damage observed in beta thalassemic and sickle (HbS) r ed blood cells. Agents that prevent heme/iron release and inhibit thei r redox activity might diminish such injury. Consequently, the inhibit ory effects of chloroquine (CQ), a heme-binding antimalarial drug, and a novel dichloroquine compound (CQ-D2) on iron release and lipid pero xidation were investigated. In contrast to normal hemoglobin, signific ant amounts of iron were released from both purified hemin and ex-hemo globin chains during incubations with exogenous reduced glutathione (G SH) and/or H2O2. Addition of either CQ or CQ-D2 effectively inhibited GSH-and GSH/H2O2-mediated iron release from hemin (P < 0.001). During prolonged incubations (6 h), both CQ and CQ-D2 significantly decreased the release of heme-free iron from both purified hemoglobin and cc-he moglobin chains. Interestingly, CQ and CQ-D2 differentially affected t he redox availability of the heme-bound iron. The CQ:heme complex sign ificantly enhanced membrane lipid peroxidation whereas CQ-D2 dramatica lly (P < 0.001) inhibited heme-dependent peroxidation to almost baseli ne levels. In summary, CC-derivatives which render heme redox inert an d prevent the release of free iron from heme might be beneficial in th e treatment of certain hemoglobinopathies and, perhaps, other patholog ies promoted by delocalized heme/iron.