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 the se drugs are known to accumulate by a weak base mechanism in the acidi c 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 trophozoit es is achieved has been subject to much discussion and argument. In th is 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 inhibit ion of heme polymerase can explain the specific toxicity of these drug s for the intraerythrocytic malaria parasite is then developed by show ing that it is consistent with much of the disparate information curre ntly available. The clinical usefulness of chloroquine, and in some re cent cases of quinine as well, has been much reduced by the evolution and spread of chloroquine resistant malaria parasites. The mechanism o f resistance involves a reduced accumulation of the drug, although aga in the mechanism involved is controversial. Possible explanations incl ude an energy-dependent efflux of preaccumulated drug via an unidentif ied transmembrane protein pump, or an increase in vacuolar pH such tha t the proton gradient responsible for drug concentration is reduced. N ew data are also presented which show that heme polymerase isolated fr om 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 si te. The significance of this result is discussed in relation to develo ping new strategies to overcome the problem presented by chloroquine r esistant malaria parasites.