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Vol. 54, Issue 1, 170-179, July 1998
Department of Pharmacology and Therapeutics (P.G.B., M.M., S.A.W.),
The University of Liverpool, Liverpool L69 3BX, UK, and
Hoffmann-La
Roche (R.G.R.), Pharmaceuticals Division, Pharma Research Preclinical,
CH-4070 Basel, Switzerland
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 (r2 = 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.
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