Abstract
The oxidation of oxyhemoglobin to methemoglobin has been found to be facilitated by low molecular weight iron(III) thiosemicarbazone complexes. This deleterious reaction, which produces hemoglobin protein units unable to bind dioxygen and occurs during the administration of iron chelators such as the well-known 3-aminopyridine-2-pyridine-carbaldehyde thiosemicarbazone (3-AP; Triapine), has been observed in the reaction with Fe-III complexes of some members of the 3-AP structurally-related thiosemicarbazone ligands derived from di-2-pyridyl ketone (HDpxxT series). We have studied the kinetics of this oxidation reaction in vitro using human hemoglobin and found that the reaction proceeds with two distinct time-resolved steps. These have been associated with sequential oxidation of the two different oxyheme cofactors in the alpha and beta protein chains. Unexpected steric and hydrogen-bonding effects on the Fe-III complexes appear to be the responsible for the observed differences in the reaction rate across the series of HDpxxT ligand complexes used in this study.