HYMENOLEPIS-DIMINUTA AND H-MICROSTOMA - UPTAKE OF CYCLOSPORINE-A AND DRUG-BINDING TO PARASITE CYCLOPHILINS

Cyclosporin A (CsA) acts as a powerful immunosuppressant through its b inding to the cytosolic isomerase, cyclophilin (CyP), forming a comple x which inhibits the phosphatase activity of calcineurin. The drug is also selectively anti-parasitic but its mode of action remains unknown . The mouse tapeform, Hymenolepis microstoma is sensitive to CsA, but the rat tapeworm, H. diminuta is not susceptible either in rats, mice or in vitro. Using these two tapeworm models, the uptake and binding o f CsA were examined in relation to parasite cyclophilins. Uptake and c ompartmentalization of the drug were markedly different in the two spe cies: H. microstoma takes up more drug than does H. diminuta and seque sters more drug into intracellular compartments. Characterization of c yclophilins using both CsA binding and isomerase activity assays revea ls that H. microstoma possesses two cyclophilin isoforms (M(r) 17700 a nd 21400) with isomerase activity that is inhibited by CsA. Using iden tical assays, we have been unable to demonstrate CsA-binding proteins or CsA-sensitive isomerase activity in H. diminuta. These data suggest that the anthelmintic action of CsA relates in some way to the presen ce and function of parasite cyclophilins.