Hymenolepis diminuta and H-microstoma: Uptake of cyclosporin A and drug binding to parasite cyclophilins

H.C. Roberts, Jeremy M Sternberg, Leslie Chappell

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cyclosporin A (CsA) acts as a powerful immunosuppressant through its binding to the cytosolic isomerase, cyclophilin (CyP), forming a complex 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 of CsA were examined in relation to parasite cyclophilins. Uptake and compartmentalization of the drug were markedly different in the two species: H. microstoma takes up more drug than does H. diminuta and sequesters more drug into intracellular compartments. Characterization of cyclophilins using both CsA binding and isomerase activity assays reveals that H. microstoma possesses two cyclophilin isoforms (M(r) 17700 and 21400) with isomerase activity that is inhibited by CsA. Using identical 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 presence and function of parasite cyclophilins.

Original languageEnglish
Pages (from-to)591-597
Number of pages7
JournalParasitology
Volume111
Issue number5
DOIs
Publication statusPublished - Dec 1995

Keywords

  • anthelmintics
  • cyclophilin
  • cyclosporin A
  • Hymenolepis diminuta
  • Hymenolepis microstoma
  • immunosuppression
  • drug uptake
  • CIS-trans isomerase
  • cyclosporine-A
  • catalysis
  • proteins
  • invivo

Cite this

Hymenolepis diminuta and H-microstoma: Uptake of cyclosporin A and drug binding to parasite cyclophilins. / Roberts, H.C.; Sternberg, Jeremy M; Chappell, Leslie.

In: Parasitology, Vol. 111, No. 5, 12.1995, p. 591-597.

Research output: Contribution to journalArticle

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abstract = "Cyclosporin A (CsA) acts as a powerful immunosuppressant through its binding to the cytosolic isomerase, cyclophilin (CyP), forming a complex 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 of CsA were examined in relation to parasite cyclophilins. Uptake and compartmentalization of the drug were markedly different in the two species: H. microstoma takes up more drug than does H. diminuta and sequesters more drug into intracellular compartments. Characterization of cyclophilins using both CsA binding and isomerase activity assays reveals that H. microstoma possesses two cyclophilin isoforms (M(r) 17700 and 21400) with isomerase activity that is inhibited by CsA. Using identical 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 presence and function of parasite cyclophilins.",
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AB - Cyclosporin A (CsA) acts as a powerful immunosuppressant through its binding to the cytosolic isomerase, cyclophilin (CyP), forming a complex 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 of CsA were examined in relation to parasite cyclophilins. Uptake and compartmentalization of the drug were markedly different in the two species: H. microstoma takes up more drug than does H. diminuta and sequesters more drug into intracellular compartments. Characterization of cyclophilins using both CsA binding and isomerase activity assays reveals that H. microstoma possesses two cyclophilin isoforms (M(r) 17700 and 21400) with isomerase activity that is inhibited by CsA. Using identical 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 presence and function of parasite cyclophilins.

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