Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

The malaria parasite feeds by degrading haemoglobin in an acidic food vacuo le, producing free haem moieties as a byproduct. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fat e of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozo in. The remainder appears to be degraded by a non-enzymic process which lea ds to an accumulation of iron in the parasite. A possible route for degrada tion of the haem is by reacting with H2O2, and we show that, under conditio ns designed to resemble those found in the food vacuole, i.e., at pH 5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposit ion. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine a quinoline compound wi th very low antimalarial activity, has little inhibitory effect. We also sh ow that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized ery throcytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activi ty by causing a build-up of toxic membrane-associated haem molecules that e ventually destroy the integrity of the malaria parasite. We have further sh own that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the wea k antimalarial activities of these compounds.