Leishmaniasis pp 495-501 | Cite as

The Sterols of Leishmania Promastigotes and Amastigotes: Possible Implications for Chemotherapy

  • L. J. Goad
  • J. S. Keithly
  • J. D. Berman
  • D. H. Beach
  • G. G. Holz
Part of the NATO ASI Series book series (NSSA, volume 171)

Abstract

The major sterol identified [1] in the promastigotes of several Leishmania species is ergosta-5,7,24(28)-trien-3β-ol (11, Fig 1) and this is often accompanied by variable amounts of ergosta-5,7,22E-trien-3β-ol (ergosterol, 12). The presence of lanosterol (1) and a range of other trace sterols (2–10) in Leishmania [1,2], together with the results of labelling studies with [2–14C]mevalonic acid [2–4], indicate that the major promastigote C28-sterols are produced by the routes shown in Fig. 1. Similar metabolic routes are operative in many fungi which elaborate ergosterol (12) as the major sterol. When Leishmania promastigotes are cultured on a medium containing serum the cells contain considerable amounts of cholest-5-en-3β-ol (cholesterol) [1, 2]. This cholesterol is derived from the serum lipoproteins and it does not appear to be metabolised by the promastigotes to C28 sterols such as 11 or 12 [2].

Keywords

Cholesterol Beach Azole Triazole Itraconazole 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    L. J. Goad, G. G. Holz and D. H. Beach, Sterols of Leishmania species. Implications for biosynthesis. Mol. Biochem. Parasitol. 10: 161–170 (1984).PubMedCrossRefGoogle Scholar
  2. 2.
    L. J. Goad, G. G. Holz and D. H. Beach, Sterols of ketoconazole-inhibited Leishmania mexicana mexicana promastiqotes. Mol. Biochem. Parasitol. 15: 257–279 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    J. D. Berman, L. J. Goad, D. H. Beach and G. G. Holz, Effects of ketoconazole on sterol biosynthesis by Leishmania mexicana mexicana amastigotes in murine macrophage tumor cells. Mol. Biochem. Parasitol. 20: 85–92 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    J. D. Berman, G. G. Holz and D. H. Beach, Effects of ketoconazole on growth and sterol biosynthesis of Leishmania promastigotes in culture. Mol. Biochem. Parasitol. 12: 1–13 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    H. B. Levine, Ketoconazole in the management of fungal disease. ADIS Press, Balgowlah, Australia (1982).Google Scholar
  6. 6.
    H. Van den Bossche, W. Lauwers, G. Willemsens, P. Marichal, F. Cornelissen and W. Cools, Molecular basis for the antimycotic and antibacterial activity of N-substituted imidazoles and triazoles: the inhibition of isoprenoid biosynthesis. Pestic. Sei. 15: 188–198 (1984).CrossRefGoogle Scholar
  7. 7.
    H. Van den Bossche, Biochemical targets for antifungal azole derivatives: Hypothesis on the mode of action. Curr. Topics in Med. Mycol. (M.R. McGinnis ed.) Vol.1, pp 313–351, Springer-Verlag, New York (1985).CrossRefGoogle Scholar
  8. 8.
    J. D. Berman, Activity of imidazoles against Leishmania tropica in human macrophage cultures. Am. J. Trop. Med. Hyg. 30: 566–569 (1981).PubMedGoogle Scholar
  9. 9.
    J. D. Berman, In vitro susceptibility of antimony resistent Leishmania to alternative drugs. J. Infect. Dis. 145: 279 (1982).PubMedCrossRefGoogle Scholar
  10. 10.
    J. D. Berman and L. S. Lee, Activity of anti-leishmanial agents against amastigotes in human monocyte-derived macrophages and in mouse peritoneal macrophages. J. Parasitol. 70: 220–225 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Raether and H. Seidenath, Ketoconazole and other potent anti-mycotic azoles exhibit pronounced activity against Trypanosoma cruzi, Plasmodium berghei and Entamoeba histolytica in vivo. Z. Parasiteuk. 70: 135–138 (1984).CrossRefGoogle Scholar
  12. 12.
    F. G. Urcuyo and N. Zaias, Oral ketoconazole in treatment of leishmaniasis. Int. J. Dermatol. 21: 414–416 (1982).PubMedCrossRefGoogle Scholar
  13. 13.
    L. Weinrauch, R. Livshin and J. El-On, Cutaneous leishmaniasis treatment with ketoconazole. Cutis 32: 288–294 (1983).PubMedGoogle Scholar
  14. 14.
    L. Weinrauch, R. Livshin, Z. Evan-Paz and J. El-On, Efficacy of ketoconazole in cutaneous leishmaniasis. Arch. Dermatol. Res. 275, 353–354 (1983).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Viallet, J. D. MacLean and H. Robson, Response to ketoconazole in two cases of longstanding cutaneous leishmaniasis. Am. J. Trop Med. Hyg. 35: 491–495 (1986).PubMedGoogle Scholar
  16. 16.
    D. Borelli, A clinical trail of itraconazole in the treatment of deep mycoses and leishmaniasis. Rev. Infect. Dis. 9: (Suppl. 1) S57–S63 (1987).CrossRefGoogle Scholar
  17. 17.
    I. J. Massey and C. Djerassi, Structure and stereochemical applications of mass spectrometry in the marine field. J. Org. Chem. 44: 2448–2456 (1979).CrossRefGoogle Scholar
  18. 18.
    C. J. W. Brooks, E. C. Horning and J. S. Young, Characterisation of sterols by gas chromatography-mass spectrometry of the trimethylsilyl ethers. Lipids 3: 391–402 (1968).PubMedCrossRefGoogle Scholar
  19. 19.
    C. J. W. Brooks, B. A. Knights, W. Sucrow and B. Raduchel, The characterisation of 24-ethylidene sterols. Steroids 20: 487–497 (1972).PubMedCrossRefGoogle Scholar
  20. 20.
    P. A. Haughan, J. R. Lenton and L. J. Goad, Paclobutrazol inhibition of sterol biosynthesis in a cell suspension culture and evidence of an essential role of 24-ethylsterol in plant cell division. Biochem. Biophys. Res. Commun. 146: 510–516 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    E. I. Mercer, The biosynthesis of ergosterol. Pestic Sci. 15: 133–155 (1984).CrossRefGoogle Scholar
  22. 22.
    R. J. Rodriguez, C. Low, C. D. K. Botema and L. W. Parks, Multiple functions for sterols in Saccharomyces cerevisiae. Biochim. Biophys. Acta 837: 336–343 (1985).PubMedCrossRefGoogle Scholar
  23. 23.
    W. J. Pinto and W. R. Nes, Stereochemical specificity for sterols in Saccharomyces cerevisiae. J. biol. Chem. 258: 4472–4476 (1983).PubMedGoogle Scholar
  24. 24.
    C. Dahl, H-P. Biemann and S. Dahl, A protein kinase antigenically related to pp60 possibly involved in yeast cell cycle control: Positive in vivo regulation by sterol. Proc. Natl. Acad. Sci. USA., 84: 4012–4016 (1987).PubMedCrossRefGoogle Scholar
  25. 25.
    W. D. Nes and R. C. Heupel, Physiological requirement for biosynthesis of multiple 243-methylsterols in Gibberella fujikuroi. Arch. Biochem. Biophys. 244: 211–217 (1986).PubMedCrossRefGoogle Scholar
  26. 26.
    R. J. Rodriguez and L. W. Parks, Structural and physiological features of sterols necessary to satisfy bulk membrane and sparking requirements in yeast sterol auxotrophs. Arch. Biochem. Biophys. 225: 861–871 (1983).PubMedCrossRefGoogle Scholar
  27. 27.
    L. J. Goad, G. G. Holz and D. H. Beach, Effect of the allylamine antifungal drug SF 86–327 on the growth and sterol synthesis of Leishmania mexicana mexicana promastigotes. Biochem. Pharmacol. 34: 3785–3788 (1985).PubMedCrossRefGoogle Scholar
  28. 28.
    L. Weinrauch and J. El-On, The effect of ketoconazole and a combination of rifampicin/amphoterin B on cutaneous leishmaniasis in laboratory mice. Trans R. Soc. Trop. Med. Hyg. 78: 389–390 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    L. Weinrauch, R. Livshin, G. P. Jacobs and J. El-On, Cutaneous leishmaniasis: failure of topical treatment with imidazole derivatives on laboratory animals and man. Arch. Dermatol Res. 276: 133–134 (1984).PubMedCrossRefGoogle Scholar
  30. 30.
    J. S. Keithly and S. G. Langreth, Inefficacy of metronidazole in experimental infections of Leishmania donovani, L. mexicana and Trypanosoma brucei brucei. Am. J. Trop. Med. Hyg. 32: 485–496 (1983).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • L. J. Goad
    • 1
  • J. S. Keithly
    • 2
  • J. D. Berman
    • 3
  • D. H. Beach
    • 4
  • G. G. Holz
    • 4
  1. 1.Department of BiochemistryUniversity of LiverpoolLiverpoolUK
  2. 2.Department of Microbiology CornellUniversity Medical CollegeNew YorkUSA
  3. 3.Division of Experimental TherapeuticsWalter Reed Army Institute of ResearchUSA
  4. 4.Department of Microbiology and Immunology, Health Science Center at SyracuseS.U.N.Y.SyracuseUSA

Personalised recommendations