2-2--azino-di-(3-ethylbenzothiazoline)-6-sulfonic-acid and artemisinin

Artemisinin, a sesquiterpene endoperoxide derived from a traditional Chinese herbal remedy for fevers, is a promising new antimalarial drug, particularly useful against multidrug resistant strains of P. falciparum. Despite widespread clinical use, its mode of action remains uncertain. We investigated whether its antimalarial properties could be explained by an ability to enhance the redox activity of heme, formed in the parasite food vacuole from digested hemoglobin. Artemisinin caused a sustained threefold increase, followed by a gradual decline, in the peroxidase activity of heme. It also enhanced the ability of heme to oxidize membrane lipids about sixfold. An unexpected finding was the potentiation of heme-catalysed membrane lipid oxidation by Vitamin E. The changes in redox-catalytic activity induced by artemisinin were paralleled by major changes in the absorption spectrum of heme, culminating in loss of the Soret band. We propose a model in which artemisinin binds irreversibly to heme in the parasite food vacuole, preventing its polymerization to chemically inert hemozoin, and promoting heme-catalysed oxidation of the vacuolar membrane by molecular oxygen, which leads, ultimately, to vacuole rupture and parasite autodigestion.

Topics: Antimalarials; Artemisinins; Artesunate; Benzothiazoles; Erythrocyte Membrane; Free Radical Scavengers; Heme; Humans; Hydrogen Peroxide; Lipid Peroxidation; Malondialdehyde; Membrane Lipids; Oxidation-Reduction; Peroxidases; Sesquiterpenes; Spectrophotometry; Sulfonic Acids; Thiobarbiturates; Vitamin E