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Molecular Pharmacology

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Research ArticleArticle

Access to Hematin: The Basis of Chloroquine Resistance

Patrick G. Bray, Mathirut Mungthin, Robert G. Ridley and Stephen A. Ward
Molecular Pharmacology July 1998, 54 (1) 170-179; DOI: https://doi.org/10.1124/mol.54.1.170
Patrick G. Bray
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Mathirut Mungthin
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Robert G. Ridley
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Stephen A. Ward
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Abstract

The saturable uptake of chloroquine by parasites of Plasmodium falciparum has been attributed to specific carrier-mediated transport of chloroquine. It is suggested that chloroquine is transported in exchange for protons by the parasite membrane Na+/H+ exchanger [J Biol Chem 272:2652–2658 (1997)]. Once inside the parasite, it is proposed that chloroquine inhibits the polymerization of hematin, allowing this toxic hemoglobin metabolite to accumulate and kill the cell [Pharmacol Ther 57:203–235 (1993)]. To date, the contribution of these proposed mechanisms to the uptake and antimalarial activity of chloroquine has not been assessed. Using sodium-free medium, we demonstrate that chloroquine is not directly exchanged for protons by the plasmodial Na+/H+exchanger. Furthermore, we show that saturable chloroquine uptake at equilibrium is due solely to the binding of chloroquine to hematin rather than active uptake: using Ro 40–4388, a potent and specific inhibitor of hemoglobin digestion and, by implication, hematin release, we demonstrate a concentration-dependent reduction in the number of chloroquine binding sites. An equal number of chloroquine binding sites are found in both resistant and susceptible clones, but the apparent affinity of chloroquine binding is found to correlate with drug activity (r 2 = 0.93, p< 0.0001). This completely accounts for both the reduced drug accumulation and activity observed in resistant clones and the “reversal” of resistance produced by verapamil. The data presented here reconcile most of the available biochemical data from studies of the mode of action of chloroquine and the mechanism of chloroquine resistance. We show that the activity of chloroquine and amodiaquine is directly dependent on the saturable binding of the drugs to hematin and that the inhibition of hematin polymerization may be secondary to this binding. The chloroquine-resistance mechanism regulates the access of chloroquine to hematin. Our model is consistent with a resistance mechanism that acts specifically at the food vacuole to alter the binding of chloroquine to hematin rather than changing the active transport of chloroquine across the parasite plasma membrane.

Footnotes

    • Received January 9, 1998.
    • Accepted March 31, 1998.
  • Send reprint requests to: Dr. Stephen. A. Ward, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3BX, UK. E-mail: saward{at}liv.ac.uk

  • This work was supported by a Research Program Grant from The Wellcome Trust.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Access to Hematin: The Basis of Chloroquine Resistance

Patrick G. Bray, Mathirut Mungthin, Robert G. Ridley and Stephen A. Ward
Molecular Pharmacology July 1, 1998, 54 (1) 170-179; DOI: https://doi.org/10.1124/mol.54.1.170

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Research ArticleArticle

Access to Hematin: The Basis of Chloroquine Resistance

Patrick G. Bray, Mathirut Mungthin, Robert G. Ridley and Stephen A. Ward
Molecular Pharmacology July 1, 1998, 54 (1) 170-179; DOI: https://doi.org/10.1124/mol.54.1.170
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