Abstract

The effects of the antiparasitic drugs levamisole, thiabendazole, chloroquine, and praziquantel on electron transport in Ascaris muscle submitochondrial particles were compared. These compounds were found to inhibit various mitochondrial NADH-oxidizing enzyme activities, including NADH oxidase and NADH-fumarate, NADH duroquinone, and NADH-cytochrome c reductases. The inhibitory effects of these drugs were the same toward both NADH oxidase and NADH-fumarate reductase activities, indicating a common inhibitory site for both enzyme systems. Evidence for the location of this inhibition site has been obtained from kinetic analyses. Inhibition of NADH oxidase activity by the drugs was found to be noncompetitive toward NADH, whereas a competitive relationship resulted in the inhibition of the enzyme-catalyzed reduction of duroquinone by NADH with respect to the quinone. This suggests that the primary sensitive site is located where the NADH dehydrogenase reduces the quinone. The failure to observe appreciable inhibition by the drugs of the mitochondrial oxidation of NADH by ferricyanide demonstrates that the drugs do not act between substrate and flavoprotein of the NADH dehydrogenase segment. With the exception of thiabendazole, the drugs did not significantly affect either succinate oxidase or succinate-cytochrome c reductase activities. Nor did the compounds significantly affect the inhibition of succinate dehydrogenase. Again with the exception of thiabendazole, reduced coenzyme Q₂-cytochrome c reductase activity of the submitochondrial particles was essentially insensitive to concentrations of inhibitors that highly diminished NADH oxidase and NADH-fumarate and NADH-duroquinone reductase activities. These results clearly assign a locus of inhibition by various anthelmintics and by chloroquine to the quinone-reducing site of the mitochondrial NADH dehydrogenase segment. Comparative studies with thiabendazole indicate that this compound is inhibitory at additional sites of the electron transport system of the parasite.