DCTP LEVELS ARE MAINTAINED IN PLASMODIUM-FALCIPARUM SUBJECTED TO PYRIMIDINE DEFICIENCY OR EXCESS

The pyrimidine antagonists, 6-L-thiodihydroorotate (TDHO) and atovaquo ne, are known to induce inhibition of de-novo pyrimidine biosynthesis in Plasmodium falciparum growing in erythrocytic culture, at reactions catalysed by dihydroorotase and dihydroorotate dehydrogenase, respect ively. In the present study, TDHO and atovaquone induced decreases in the levels of UTP, CTP and dTTP but not dCTP in P. falciparum. Additio n of orotate with either antagonist increased UTP, CTP and dTTP but de pressed GTP, ATP, dATP and dCTP, suggesting that these drugs indirectl y modulate the activity of ribonucleotide reductase. The changes induc ed in the levels of dNTP by these pyrimidine antagonists are similar t o those previously described for the antifolates, cycloguanil and WR99 210.