Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum.
Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Although these drugs are known to accumulate by a weak base mechanism in the acidic food vacuoles of intraerythrocytic trophozoites and thereby prevent hemoglobin degradation from occurring in that organelle, the mechanism by which their selective toxicity for lysosomes of malaria trophozoites is achieved has been subject to much discussion and argument. In this review the recent discovery that chloroquine and related quinolines inhibit the novel heme polymerase enzyme that is also present in the trophozoite food vacuole is introduced. The proposal that this inhibition of heme polymerase can explain the specific toxicity of these drugs for the intraerythrocytic malaria parasite is then developed by showing that it is consistent with much of the disparate information currently available. The clinical usefulness of chloroquine, and in some recent cases of quinine as well, has been much reduced by the evolution and spread of chloroquine resistant malaria parasites. The mechanism of resistance involves a reduced accumulation of the drug, although again the mechanism involved is controversial. Possible explanations include an energy-dependent efflux of preaccumulated drug via an unidentified transmembrane protein pump, or an increase in vacuolar pH such that the proton gradient responsible for drug concentration is reduced. New data are also presented which show that heme polymerase isolated from chloroquine resistant trophozoites retains full sensitivity to drug inhibition, consistent with the observation that resistance involves a reduced accumulation of the drug at the (still vulnerable) target site. The significance of this result is discussed in relation to developing new strategies to overcome the problem presented by chloroquine resistant malaria parasites.
Slater
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AF
Picower Institute for Medical Research, Manhasset, NY 11030.
D000818:Animals; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects*
D002738:Chloroquine