Possible mode of action of toltrazuril: studies on two Eimeria species and mammalian and Ascaris suum enzymes.
The anticoccidial properties of toltrazuril in Eimeria falciformis-infected mice were potentiated by the simultaneous application of pyrimethamine, trimethoprim, or sulfadimidine. The same drugs potentiate the effect of toltrazuril by killing E. tenella schizonts in chicken kidney-cell cultures. Activities of some enzymes of the respiratory chain, such as succinate-cytochrome C reductase and NADH oxidase and succinate oxidase from mouse liver, were reduced in the presence of toltrazuril. The same effects could be observed when the activities of NADH oxidase and fumarate reductase from the nematode Ascaris suum were determined in the presence of the drug. Vertebrate enzymes involved in pyrimidine synthesis, e.g., dihydrofolate reductase from chicken liver, were also affected by toltrazuril; however, this effect was 500 times weaker than that shown by pyrimethamine. Toltrazuril also showed an inhibitory effect on the dihydroorotate-cytochrome C reductase from mouse liver. Our results suggest that toltrazuril primarily affects the respiratory chain and secondarily, two enzymes involved in pyrimidine synthesis.
Harder
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Bayer AG, Institut für Parasitologie, Leverkusen, Federal Republic of Germany.
Haberkorn
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D000818:Animals; D001200:Ascaris / Q000201:enzymology*; D002645:Chickens; D003048:Coccidiosis / Q000188:drug therapy*; D003049:Coccidiostats / Q000494:pharmacology* / Q000627:therapeutic use; D000090722:Dihydroorotate Dehydrogenase; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004539:Eimeria / Q000187:drug effects*; D005493:Folic Acid Antagonists; D051379:Mice; D008930:Mitochondria, Liver / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D013384:Succinate Cytochrome c Oxidoreductase / Q000037:antagonists & inhibitors; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013418:Sulfamethazine / Q000494:pharmacology / Q000627:therapeutic use; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use; D014295:Trimethoprim / Q000494:pharmacology / Q000627:therapeutic use
D003049:Coccidiostats; D000090722:Dihydroorotate Dehydrogenase; D005493:Folic Acid Antagonists; D009097:Multienzyme Complexes; D014227:Triazines; D013418:Sulfamethazine; D014295:Trimethoprim; D010088:Oxidoreductases; D013384:Succinate Cytochrome c Oxidoreductase; C022691:succinate oxidase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D013385:Succinate Dehydrogenase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; C036670:toltrazuril; D011739:Pyrimethamine