Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators.
To examine the site of action of antimalarial iron chelators, iron ligands were added to control erythrocytes and to erythrocytes parasitized with Plasmodium falciparum, and the concentration of intracellular labile iron was monitored with the fluorescent probe, calcein. The fluorescence of calcein quenches upon binding iron and increases upon releasing iron. The chelators included desferrioxamine B, 2',2'-bipyridyl, and aminophenol II, a compound that is being newly reported as having anti-plasmodial properties. Calcein-loaded parasitized cells displayed fluorescence predominantly within the cytosol of both rings and trophozoites. The addition of chelators to both control and parasitized erythrocytes led to significant increases of fluorescence (P < 0.001). Fluorescence was observed to increase within the parasite itself after addition of iron chelators, indicating that these agents bound labile iron within the plasmodium. The relative increases of fluorescence after addition of chelators were greater in control than parasitized erythrocytes (P < 0.05) as were the estimated labile iron concentrations (P < or = 0.001). These results suggest that (i) the anti-malarial action of iron chelators might result from the ability to reach the infected cell's parasite compartment and bind iron within the parasite cytosol, and (ii) the labile iron pool of the host red cell may be either utilized or stored during plasmodial growth.
Department of Medicine, The George Washington University Medical Center, Washington, DC 20037, USA. loyevsky@gwis2.circ.gwu.edu
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M
Loyevsky
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C
John
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B
Dickens
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Hu
J H
JH
Miller
V R
VR
Gordeuk
D015082:2,2'-Dipyridyl / Q000378:metabolism / Q000494:pharmacology; D000627:Aminophenols / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005452:Fluoresceins / Q000378:metabolism / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*
D000627:Aminophenols; D002614:Chelating Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D015082:2,2'-Dipyridyl; D007501:Iron; D003676:Deferoxamine; D002118:Calcium; C007740:fluorexon