Deferoxamine: stimulation of hematin polymerization and antagonism of its inhibition by chloroquine.
The iron chelator deferoxamine enhances the clearance of Plasmodium falciparum parasitemia and may be useful in drug combinations for the treatment of cerebral malaria. However, the deferoxamine-chloroquine drug combination is antagonistic, or at best additive, against P. falciparum in vitro. As chloroquine is thought to exert its antimalarial activity by interacting with hematin released from the proteolytic degradation of hemoglobin in the parasite food vacuole, we hypothesized that deferoxamine might interfere with the ability of chloroquine to inhibit hematin polymerization, since it was reported that deferoxamine interacts with hematin. Therefore, we assessed deferoxamine-hematin binding in more detail and investigated the effect of deferoxamine on hematin polymerization in the presence and absence of chloroquine. Isothermal titration calorimetry (ITC) experiments demonstrated an enthalpy-driven deferoxamine:hematin mu-oxo dimer binding with an association constant of 2.8 x 10(4) M(-1) at pH 6.5, a binding affinity 14-fold lower than that measured for chloroquine. At least two of the three hydroxamic acid functional groups of deferoxamine must be unionized for effective binding. We also discovered that deferoxamine antagonized chloroquine-mediated inhibition of hematin polymerization. Unexpectedly, deferoxamine increased the concentration of soluble forms of hematin and enhanced the rate of hematin polymerization. Deferoxamine also could initiate hematin polymerization. In contrast, chloroquine decreased the concentration of soluble forms of hematin and inhibited hematin polymerization. This work supports the postulate that initiation of hematin polymerization requires a higher concentration of soluble hematin monomer than does the elongation phase of polymerization and provides one possible explanation for the observed antagonism between deferoxamine and chloroquine against parasites in culture.
Vippagunta
S R
SR
University of Nebraska Medical Center, College of Pharmacy, Omaha 68198-6025, USA.
Dorn
A
A
Bubendorf
A
A
Ridley
R G
RG
Vennerstrom
J L
JL
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001704:Biopolymers / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D002738:Chloroquine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology*; D004347:Drug Interactions; D006427:Hemin / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology; D012995:Solubility / Q000187:drug effects
D000962:Antimalarials; D001704:Biopolymers; D002614:Chelating Agents; D006427:Hemin; D002738:Chloroquine; D003676:Deferoxamine