title: Pharmacologic interception of heme: a potential therapeutic strategy for the treatment of β thalassemia?
abstract: Pro-oxidant effects of hemoglobin-derived heme and iron contribute to the progressive damage observed in β thalassemic and sickle (HbS) red blood cells. Agents that prevent heme/iron release and inhibit their redox activity might diminish such injury. Consequently, the inhibitory effects of chloroquine (CQ), a heme-binding antimalarial drug, and a novel dichloroquine compound (CQ-D2) on iron release and lipid peroxidation were investigated. In contrast to normal hemoglobin, significant amounts of iron were released from both purified hemin and α-hemoglobin chains during incubations with exogenous reduced glutathione (GSH) 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 α-hemoglobin chains. Interestingly, CQ and CQ-D2 differentially affected the redox availability of the heme-bound iron. The CQ: heme complex significantly enhanced membrane lipid peroxidation whereas CQ-D2 dramatically (P<0.001) inhibited heme-dependent peroxidation to almost baseline levels. In summary, CQ-derivatives which render heme redox inert and prevent the release of free iron from heme might be beneficial in the treatment of certain hemoglobinopathies and, perhaps, other pathologies promoted by delocalized heme/iron.
authors.affiliation: a Department of Pathology and Laboratory Medicine , Albany Medical College , Albany , NY.
authors.forename: M D
authors.initials: MD
authors.lastname: Scott
authors.affiliation: b The Picower Institute for Medical Research , Manhasset, NY , USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: b The Picower Institute for Medical Research , Manhasset, NY , USA.
authors.forename: P
authors.initials: P
authors.lastname: Ulrich
authors.affiliation: a Department of Pathology and Laboratory Medicine , Albany Medical College , Albany , NY.
authors.forename: T
authors.initials: T
authors.lastname: Shupe