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Kinetic studies on the oxidation of oxyhemoglobin by biologically active iron thiosemicarbazone complexes: relevance to iron-chelator-induced methemoglobinemia

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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-pyridinecarbaldehyde thiosemicarbazone (3-AP; Triapine), has been observed in the reaction with FeIII 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 α and β protein chains. Unexpected steric and hydrogen-bonding effects on the FeIII 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.

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Abbreviations

3-AP:

3-Amino-2-pyridinecarboxaldehyde thiosemicarbazone

DeoxyHb:

Deoxyhemoglobin

DFO:

Desferrioxamine B

Hb:

Hemoglobin

HbO2 :

Oxyhemoglobin

HDpT:

Di-2-pyridyl ketone thiosemicarbazone

HDp4eT:

Di-2-pyridyl ketone 4-ethylthiosemicarbazone

HDp4mT:

Di-2-pyridylketone 4-methylthiosemicarbazone

HDp44mT:

Di-2-pyridyl ketone 4,4-dimethylthiosemicarbazone

MetHb:

Methemoglobin

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Acknowledgments

Financial support from the Australian Research Council (P.V.B.), the National Health and Medical Research Council of Australia (project grants and a Senior Principal Research Fellowship to D.R.R.), and the Spanish Ministerio de Ciencia e Innovación (CTQ2012-37821-C02-01, C.R., M.M., and P.V.B.) is gratefully acknowledged. M.T.B. is grateful for scholarship support from King Abdul Aziz University (Jeddah, Saudi Arabia).

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Correspondence to Paul V. Bernhardt.

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Basha, M.T., Rodríguez, C., Richardson, D.R. et al. Kinetic studies on the oxidation of oxyhemoglobin by biologically active iron thiosemicarbazone complexes: relevance to iron-chelator-induced methemoglobinemia. J Biol Inorg Chem 19, 349–357 (2014). https://doi.org/10.1007/s00775-013-1070-9

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