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© The Rockefeller University Press, 0021-9525/1999//363 $5.00
The Journal of Cell Biology, Volume 145, Number 2, , 1999 363-376

Regular Articles

Cellular Uptake of Chloroquine Is Dependent on Binding to Ferriprotoporphyrin IX and Is Independent of NHE Activity in Plasmodium falciparum



Patrick G. Bray*, Omar Janneh*, Kaylene J. Raynes*, Mathirut Mungthin*, Hagai Ginsburg{ddagger}, and Stephen A. Ward*

* Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3BX, United Kingdom; and {ddagger} Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Here we provide definitive evidence that chloroquine (CQ) uptake in Plasmodium falciparum is determined by binding to ferriprotoporphyrin IX (FPIX). Specific proteinase inhibitors that block the degradation of hemoglobin and stop the generation of FPIX also inhibit CQ uptake. Food vacuole enzymes can generate cell-free binding, using human hemoglobin as a substrate. This binding accounts for CQ uptake into intact cells and is subject to identical inhibitor specificity. Inhibition of CQ uptake by amiloride derivatives occurs because of inhibition of CQ–FPIX binding rather than inhibition of the Na+/H+ exchanger (NHE). Inhibition of parasite NHE using a sodium-free medium does not inhibit CQ uptake nor does it alter the ability of amilorides to inhibit uptake. CQ resistance is characterized by a reduced affinity of CQ–FPIX binding that is reversible by verapamil. Diverse compounds that are known to disrupt lysosomal pH can mimic the verapamil effect. These effects are seen in sodium-free medium and are not due to stimulation of the NHE. We propose that these compounds increase CQ accumulation and overcome CQ resistance by increasing the pH of lysosomes and endosomes, thereby causing an increased affinity of binding of CQ to FPIX.

Key Words: Plasmodium falciparum • chloroquine • drug resistance • heme binding • Na+/H+ exchanger

Abbreviations used in this paper: AQ, amodiaquine; CQ, chloroquine; CQR, chloroquine-resistant; CQS, chloroquine-sensitive; FPIX, ferriprotoporphyrin IX; HB7, Hepes buffer at pH 7; NHE, Na+/H+ exchanger.


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