J. Cell Biol., Volume 145, Number 2, April 19, 1999 363-376

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, and Stephen A. Ward^*

^* Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3BX, United Kingdom; and  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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Bousejra-El Garah, F., Claparols, C., Benoit-Vical, F., Meunier, B., Robert, A. (2008). The Antimalarial Trioxaquine DU1301 Alkylates Heme in Malaria-Infected Mice. Antimicrob. Agents Chemother. 52: 2966-2969 [Abstract] [Full Text]  
• Lehane, A. M., Hayward, R., Saliba, K. J., Kirk, K. (2008). A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites. J. Cell Sci. 121: 1624-1632 [Abstract] [Full Text]  
• Biagini, G. A., Fisher, N., Berry, N., Stocks, P. A., Meunier, B., Williams, D. P., Bonar-Law, R., Bray, P. G., Owen, A., O'Neill, P. M., Ward, S. A. (2008). Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrial bc1 Complex. Mol. Pharmacol. 73: 1347-1355 [Abstract] [Full Text]  
• Fivelman, Q. L., Adagu, I. S., Warhurst, D. C. (2007). Effects of Piperaquine, Chloroquine, and Amodiaquine on Drug Uptake and of These in Combination with Dihydroartemisinin against Drug-Sensitive and -Resistant Plasmodium falciparum Strains. Antimicrob. Agents Chemother. 51: 2265-2267 [Abstract] [Full Text]  
• Richier, E., Biagini, G. A., Wein, S., Boudou, F., Bray, P. G., Ward, S. A., Precigout, E., Calas, M., Dubremetz, J.-F., Vial, H. J. (2006). Potent Antihematozoan Activity of Novel Bisthiazolium Drug T16: Evidence for Inhibition of Phosphatidylcholine Metabolism in Erythrocytes Infected with Babesia and Plasmodium spp.. Antimicrob. Agents Chemother. 50: 3381-3388 [Abstract] [Full Text]  
• Hayward, R., Saliba, K. J., Kirk, K. (2006). The pH of the digestive vacuole of Plasmodium falciparum is not associated with chloroquine resistance. J. Cell Sci. 119: 1016-1025 [Abstract] [Full Text]  
• Andrews, K. T., Fairlie, D. P., Madala, P. K., Ray, J., Wyatt, D. M., Hilton, P. M., Melville, L. A., Beattie, L., Gardiner, D. L., Reid, R. C., Stoermer, M. J., Skinner-Adams, T., Berry, C., McCarthy, J. S. (2006). Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria. Antimicrob. Agents Chemother. 50: 639-648 [Abstract] [Full Text]  
• Prade, L., Jones, A. F., Boss, C., Richard-Bildstein, S., Meyer, S., Binkert, C., Bur, D. (2005). X-ray Structure of Plasmepsin II Complexed with a Potent Achiral Inhibitor. J. Biol. Chem. 280: 23837-23843 [Abstract] [Full Text]  
• Liu, J., Gluzman, I. Y., Drew, M. E., Goldberg, D. E. (2005). The Role of Plasmodium falciparum Food Vacuole Plasmepsins. J. Biol. Chem. 280: 1432-1437 [Abstract] [Full Text]  
• Winstanley, P., Ward, S., Snow, R., Breckenridge, A. (2004). Therapy of Falciparum Malaria in Sub-Saharan Africa: from Molecule to Policy. Clin. Microbiol. Rev. 17: 612-637 [Abstract] [Full Text]  
• Hoppe, H. C., van Schalkwyk, D. A., Wiehart, U. I. M., Meredith, S. A., Egan, J., Weber, B. W. (2004). Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum. Antimicrob. Agents Chemother. 48: 2370-2378 [Abstract] [Full Text]  
• Waller, K. L., Muhle, R. A., Ursos, L. M., Horrocks, P., Verdier-Pinard, D., Sidhu, A. B. S., Fujioka, H., Roepe, P. D., Fidock, D. A. (2003). Chloroquine Resistance Modulated in Vitro by Expression Levels of the Plasmodium falciparum Chloroquine Resistance Transporter. J. Biol. Chem. 278: 33593-33601 [Abstract] [Full Text]  
• Biagini, G. A., Richier, E., Bray, P. G., Calas, M., Vial, H., Ward, S. A. (2003). Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums. Antimicrob. Agents Chemother. 47: 2584-2589 [Abstract] [Full Text]  
• Nzila, A., Mberu, E., Bray, P., Kokwaro, G., Winstanley, P., Marsh, K., Ward, S. (2003). Chemosensitization of Plasmodium falciparum by Probenecid In Vitro. Antimicrob. Agents Chemother. 47: 2108-2112 [Abstract] [Full Text]  
• Zhang, H., Howard, E. M., Roepe, P. D. (2002). Analysis of the Antimalarial Drug Resistance Protein Pfcrt Expressed in Yeast. J. Biol. Chem. 277: 49767-49775 [Abstract] [Full Text]  
• Wissing, F., Sanchez, C. P., Rohrbach, P., Ricken, S., Lanzer, M. (2002). Illumination of the Malaria Parasite Plasmodium falciparum Alters Intracellular pH. IMPLICATIONS FOR LIVE CELL IMAGING. J. Biol. Chem. 277: 37747-37755 [Abstract] [Full Text]  
• Pradines, B., Alibert, S., Houdoin, C., Santelli-Rouvier, C., Mosnier, J., Fusai, T., Rogier, C., Barbe, J., Parzy, D. (2002). In Vitro Increase in Chloroquine Accumulation Induced by Dihydroethano- and Ethenoanthracene Derivatives in Plasmodium falciparum-Parasitized Erythrocytes. Antimicrob. Agents Chemother. 46: 2061-2068 [Abstract] [Full Text]  
• Mehlotra, R. K., Fujioka, H., Roepe, P. D., Janneh, O., Ursos, L. M. B., Jacobs-Lorena, V., McNamara, D. T., Bockarie, M. J., Kazura, J. W., Kyle, D. E., Fidock, D. A., Zimmerman, P. A. (2001). Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc. Natl. Acad. Sci. USA 98: 12689-12694 [Abstract] [Full Text]  
• Taramelli, D., Tognazioli, C., Ravagnani, F., Leopardi, O., Giannulis, G., Boelaert, J. R. (2001). Inhibition of Intramacrophage Growth of Penicillium marneffei by 4-Aminoquinolines. Antimicrob. Agents Chemother. 45: 1450-1455 [Abstract] [Full Text]  
• Stead, A. M. W., Bray, P. G., Edwards, I. G., DeKoning, H. P., Elford, B. C., Stocks, P. A., Ward, S. A. (2001). Diamidine Compounds: Selective Uptake and Targeting in Plasmodium falciparum. Mol. Pharmacol. 59: 1298-1306 [Abstract] [Full Text]  
• Kirk, K. (2001). Membrane Transport in the Malaria-Infected Erythrocyte. Physiol. Rev. 81: 495-537 [Abstract] [Full Text]  
• Gekle, M., Freudinger, R., Mildenberger, S. (2001). Inhibition of Na+--H+ exchanger-3 interferes with apical receptor-mediated endocytosis via vesicle fusion. J. Physiol. 531: 619-629 [Abstract] [Full Text]  
• Taylor, D., Walden, J. C., Robins, A. H., Smith, P. J. (2000). Role of the Neurotransmitter Reuptake-Blocking Activity of Antidepressants in Reversing Chloroquine Resistance In Vitro in Plasmodium falciparum. Antimicrob. Agents Chemother. 44: 2689-2692 [Abstract] [Full Text]  
• Haruki, K., Bray, P. G., Ono, M., Ward, S. A. (2000). Potent Enhancement of the Sensitivity of Plasmodium falciparum to Chloroquine by the Bisbenzylisoquinoline Alkaloid Cepharanthin. Antimicrob. Agents Chemother. 44: 2706-2708 [Abstract] [Full Text]  
• Saliba, K. J., Kirk, K. (1999). pH Regulation in the Intracellular Malaria Parasite, Plasmodium falciparum. H+ EXTRUSION VIA A V-TYPE H+-ATPase. J. Biol. Chem. 274: 33213-33219 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents