The Mechanism of Antimalarial Action of Artemisinin (Qinghaosu)

Summary

A marked antagonism in antimalarial (Plasmodium falciparum) activity was found for combination of artemisinin or arteether with desferrioxamine. The result suggests a possible involvement of iron in the generation of reactive oxygen intermediates initiated by artemisinin or its derivative. The role of intracellular antioxidant mechanism in parasite defence against the drugs was also studied. Buthionine sulfoximine, an inhibitor of γ-glutamylcysteine synthase, an enzyme involved in glutathione synthesis was used in combination with arteether and artesunate. A synergistic effect was observed with artesunate at all concentrations, while for arteether a synergistic effect was observed at the concentrations where the inhibitor alone had little effect on the malaria parasite, while an antagonistic effect was found at higher concentrations. Diethyldithiocarbamate, an inhibitor of Superoxide dismutase, also showed a similar biphasic effect in combination with artemisinin. These results suggest that intracellular antioxidant mechanism may be important in countering the antimalarial effect of artemisinin and its derivatives. They further imply that artemisinin and its derivatives exerted antimalarial action through the oxidant mode.