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Hymenolepis diminuta and H. microstoma: uptake of cyclosporin A and drug binding to parasite cyclophilins

Published online by Cambridge University Press:  06 April 2009

H. C. Roberts ,
J. M. Sternberg  and
L. H. Chappell
H. C. Roberts
Affiliation:
Department of Zoology, University of Aberdeen, Tillydrone Avenue, Aberdeen AB9 2TN, Scotland
J. M. Sternberg
Affiliation:
Department of Zoology, University of Aberdeen, Tillydrone Avenue, Aberdeen AB9 2TN, Scotland
L. H. Chappell
Affiliation:
Department of Zoology, University of Aberdeen, Tillydrone Avenue, Aberdeen AB9 2TN, Scotland
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Summary

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 tapeworm, 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 (Mr 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.

Keywords

anthelminticscyclophilincyclosporin AHymenolepis diminutaHymenolepis microstomaimmuno-suppressiondrug uptake
Type
Research Article
Information
Parasitology , Volume 111 , Issue 5 , December 1995 , pp. 591 - 597
Copyright
Copyright © Cambridge University Press 1995

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References

REFERENCES

Bradford, M. M. (1976). A rapid and sensitive method for the quantification of microgram quantities of protein utilising the principle of protein-dye binding. Annals of Biochemistry 72, 248–54.CrossRefGoogle Scholar
Chappell, L. H. & Wastling, J. M. (1992). Cyclosporin A: antiparasitic drug, modulator of the host-parasite relationship and immunosuppressant. Parasitology 105 (Suppl.), S25–S40.CrossRefGoogle ScholarPubMed
Chappell, L. H., Wastling, J. M. & Hurd, H. (1989). Action of cyclosporin A on the tapeworms Hymenolepis microstoma, H. diminuta and Mesocestoides corti in vivo. Parasitology 98, 291–9.CrossRefGoogle ScholarPubMed
Compton, L. A., Davis, J. M., Macdonald, J. R. & Bachinger, H. P. (1992). Structural and functional characterization of Escherichia coli peptidyl-prolyl cis-trans isomerases. European Journal of Biochemistry 206, 927–34.CrossRefGoogle ScholarPubMed
Fischer, G., Bang, H. & Mech, C. (1984). Detection of enzyme catalysis for cis-trans isomerisation of peptide bonds using proline-containing peptides as substrates. Biomedica et Biochimica Acta 43, 1101–11.Google Scholar
Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X. (1989). Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature, London 337, 476–8.CrossRefGoogle ScholarPubMed
Flanagan, W. M., Corthesy, B., Bram, R. J. & Crabtree, G. R. (1991). Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature, London 352, 803–7.CrossRefGoogle ScholarPubMed
Harrison, R. K. & Stein, R. L. (1990). Mechanistic studies of peptidyl prolyl cis-trans isomerase: evidence for catalysis by distortion. Biochemistry 29, 1684–9.CrossRefGoogle ScholarPubMed
High, K. P. (1994). The antimicrobial activities of cyclosporine, FK506 and rapamycin. Transplantation 57, 1689–700.CrossRefGoogle ScholarPubMed
High, K. P., Joiner, K. A. & Handschumacher, R. E. (1994). Isolation, cDNA sequences, and biochemical characterisation of the major cyclosporin-binding proteins of Toxoplasma gondii. Journal of Biological Chemistry 269, 9105–12.CrossRefGoogle ScholarPubMed
Kallen, J., Spitzfaden, C., Zurini, M. G. M., Wider, G., Widmer, H., Wuthrich, K. & Walkinshaw, M. D. (1991). Structure of human cyclophilin and its binding site for cyclosporin A determined by X-ray crystallography and NMR spectroscopy. Nature, London 353, 276–9.CrossRefGoogle ScholarPubMed
Ke, H., Zhao, Y., Luo, F., Weissman, I. & Friedman, J. (1993). Crystal structure of murine cyclophilin C complexed with immunosuppressive drug cyclosporin A. Proceedings of the National Academy of Sciences, USA 90, 11850–4.CrossRefGoogle ScholarPubMed
Koletsky, A. J., Harding, M. W. & Handschumacher, R. E. (1986). Cyclophilin: Distribution and variant properties in normal and neoplastic tissues. Journal of Immunology 137, 1054–9.CrossRefGoogle ScholarPubMed
Koser, P. L., Livi, G. P., Levy, M. A., Rosenberg, M. & Bergsma, D. J. (1990). Candida albicans homolog of a human cyclophilin gene encodes a peptidyl prolyl cis-trans isomerase. Gene 96, 189–95.CrossRefGoogle ScholarPubMed
Lightowlers, M. W., Haralambous, A. & Rickard, M. D. (1989). Amino acid sequence homology between cyclophilin and a cDNA-cloned antigen of Echinococcus granulosus. Molecular and Biochemical Parasitology 36, 287–90.CrossRefGoogle Scholar
Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I. & Schreiber, S. L. (1991). Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP-FK506 complexes. Cell 66, 807–15.CrossRefGoogle ScholarPubMed
Merker, M. & Handschumacher, R. E. (1984). Uptake and nature of the intracellular binding of cyclosporin A in a murine thymoma cell line, BW5147. Journal of Immunology 132, 3064–70.CrossRefGoogle Scholar
Merril, C. R., Goldman, D., Sedman, S. A. & Ebert, M. H. (1981). Ultrasensitive stain for proteins in polyacrylamide gels shows regional variation in cerebrospinal fluid proteins. Science 211, 1437–8.CrossRefGoogle ScholarPubMed
Nussler, A. K. & Thomson, A. W. (1992). Immunomodulatory agents in the laboratory and clinic. Parasitology 105 (Suppl.), S5–S24.CrossRefGoogle ScholarPubMed
Read, C. P., Rothman, A. H. & Simmons, J. E. (1963). Studies on membrane transport, with special reference to parasite–host integration. Annals of the New York Academy of Sciences 113, 154–204.CrossRefGoogle ScholarPubMed
Wastling, J. M., Gerhard, D., Walker, J. & Chappell, L. H. (1990). Action of cyclosporin A on the tapeworm Hymenolepis diminuta in mice. Parasitology 101, 465–72.CrossRefGoogle ScholarPubMed
Wastling, J. M., Mackenzie, K. & Chappell, L. H. (1992). Effects of cyclosporin A on the morphology and tegumentary ultrastructure of Hymenolepis microstoma in vivo. Parasitology 104, 531–8.CrossRefGoogle ScholarPubMed