Defective transport of pyrazolopyrimidine ribosides in insensitive Trypanosoma cruzi wild strains is a parasite-stage specific and reversible characteristic.
1. By using freshly isolated blood trypomastigotes of twelve T. cruzi wild type strains we have found eight strains sensitive to FoB and FoA, while four and one were FoA- and FoB-insensitive respectively to the drug-mediated growth inhibition. 2. This was not so for APPR, to which most strains were transitory insensitive except two which were clearly sensitive. 3. All these pyrazolopyrimidines blocked trypomastigote-amastigote transformation. 4. Incubation of pyrazolopyrimidine-insensitive wild strains with [3H]FoA, [3H]FoB and [14C]APPR respectively indicates that insensitive cells can only accumulate low concentrations of phosphorylated metabolites. 5. This is due to a defective or impaired pyrazolopyrimidine riboside transport system in the wild type insensitive cells, as we did not detect significant variations in the levels of the various nucleoside and nucleobase metabolism enzymes studied. 6. Additional experiments suggested that FoA and FoB are incorporated by different nucleoside transport systems, as Y and ES strains were FoA-insensitive but FoB-sensitive. 7. Epimastigotes of the same T. cruzi strains were highly sensitive to low concentrations of the three pyrazolopyrimidine ribosides studied. However, when this parasitic form was allowed to transform into trypomastigotes, these cells showed the same pyrazolopyrimidine sensitivity found before, suggesting that in T. cruzi pyrazolopyrimidine riboside-insensitivity is a parasite-stage specific and reversible biochemical characteristic.
D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D004351:Drug Resistance; D005573:Formycins / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D010770:Phosphotransferases / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000378:metabolism* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D000981:Antiprotozoal Agents; D005573:Formycins; D011741:Pyrimidine Nucleosides; C034561:formycin B; C004420:4-aminopyrazolo(3,4-d)pyrimidine; C034550:formycin; D010770:Phosphotransferases; D000248:Adenosine Kinase; C021892:nucleoside phosphotransferase; D000225:Adenine; D000241:Adenosine