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Parasite uptake of desferroxamine: a prerequisite for antimalarial activity
Author(s) -
Scott Mark D.,
Ranz Allen,
Kuypers Frans A.,
Lubin Bertram H.,
Meshnick Steven R.
Publication year - 1990
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1990.tb07805.x
Subject(s) - extracellular , chelation , dextran , lysis , pharmacology , chemistry , biological activity , biology , biochemistry , in vitro , organic chemistry
S ummary . Desferroxamine has been shown to exhibit potent antimalarial activity. However, it is unclear as to whether desferroxamine functions by the chelation of extracellular, intra‐erythrocytic, or parasite‐associated iron. In order to determine desferroxamine's site of action, we have employed a large molecular weight dextran derivative of desferroxamine (70 kDa) and a reversible osmotic lysis technique by which erythrocytes were intracellularly loaded with this chelator. The desferroxamine‐dextran derivative has virtually identical iron‐binding characteristics to desferroxamine but, unlike desferroxamine, it is unable to cross the erythrocyte membrane. As previously shown, desferroxamine added to culture media exhibited potent antimalarial activity (mean effective inhibitory dose (ED 50 ) ∼ 6 μ m ). However, extracellular desferroxamine‐dextran showed anti‐malarial activity only at very high doses (ED 50 ≥180 μ m ), indicating that extracellular iron chelation is not involved in the antimalarial activity of desferroxamine. The intra‐erythrocytic entrapment of the desferroxamine‐dextran derivative also had no significant effect, except at very high concentrations, demonstrating that desferroxamine does not remove a non‐haem iron source necessary for malarial replication. The results of this study clearly suggests that the antimalarial activity of desferroxamine is directly related to its ability to enter the parasitic compartment and not due to the chelation of extra‐ or intra‐erythrocytic iron pools necessary for malarial growth.