THE EFFECTS OF ANTIMALARIALS ON THE PLASMODIUM-FALCIPARUM DIHYDROOROTATE DEHYDROGENASE

Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimid ine biosynthesis and the major source of electrons for the mitochondri al electron transport chain of intraerythrocytic malaria parasites. DH OD and the electron transport chain may also be the site of inhibition by certain antimalarial drugs. In order to test this, Plasmodium falc iparum-infected erythrocytes were exposed in vitro to artemisinin or v arious 8-aminoquinolines, such as primaquine, WR 238605, WR 225448, an d WR 255956, and then assayed for both enzyme activity and [H-3]hypoxa nthine incorporation, which is an indicator of viability. Atovaquone i nhibits DHOD activity to a much greater extent than hypoxanthine incor poration, which is consistent with previous reports that it targets th e parasite respiratory chain. However, artemisinin and the 8-aminoquin olines inhibit DHOD to the same or lesser extent than hypoxanthine inc orporation, suggesting that these compounds have different modes of ac tion. (C) 1994 Academic Press, Inc.