Lipids

, Volume 13, Issue 10, pp 708–715

Cyclopamine and related steroidal alkaloid teratogens: Their occurrence, structural relationship, and biologic effects

  • Richard F. Keeler
Symposium: Function of Steroids and Other Isopentenoid

Abstract

A spontaneous congenital deformity is produced in lambs whose dams consumeVeratrum californicum on the 14th day of gestation. The deformity is generally expressed as cyclopia, cebocephaly, anophthalmia, or microphthalmia. This teratogenic effect is produced by certain steroidal alkaloid teratogens from the plant—most notably the compound cyclopamine. Cyclopamine is a C-nor-D-homo steroid with fused furanopiperidine rings E and F at right angles to the plane of the steroid because of spiro attachment at C-17 of the steroid. Among veratrum alkaloids, only those with an intact furan ring E were teratogenic in sheep, whereas those in which the piperidine ring is not rigidly positioned at right angles to the steroid were not. Many ruminants and laboratory animals are susceptible to the teratogen. It has wide species and tissue specificity and appears to have a direct effect on the embryo, not as a consequence of metabolic alteration of its structure nor as an indirect effect through a maternal influence. Other plant sources, notably potatoes, tomatoes, and eggplant contain related spirosolane steroidal alkaloids. Among naturally occurring spirosolanes, solasodine is teratogenic in hamsters, but neither tomatidine not diosgenin, the non-nitrogen containing analog of solasodine, is teratogenic. Results of these and other studies suggest that a basic nitrogen positioned α with respect to the steroidal plane and at appropriate distance beyond the D ring confers the teratogenicity on the molecule. Potato sprouts with high alkaloid content are teratogenic in hamsters, but tubers and peels are not.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Binns, W., E.J. Thacker, L.F. James, and W.T. Huffman, J. Am. Vet. Med. Assoc. 134:180 (1959).PubMedGoogle Scholar
  2. 2.
    Binns, W., W.A. Anderson, and D.J. Sullivan, J. Am. Vet. Med. Assoc. 137:515 (1960).Google Scholar
  3. 3.
    Binns, W., L.F. James, J.L. Shupe, and E.J. Thacker, Arch. Environ. Health 5:106 (1962).PubMedGoogle Scholar
  4. 4.
    Binns, W., L.F. James, J.L. Shupe, and G. Everett, Am. J. Vet. Res. 24:1164 (1963).PubMedGoogle Scholar
  5. 5.
    Binns, W., J.L. Shupe, R.F. Keeler, and L.F. James, J. Am. Vet. Med. Assoc. 147:839 (1965).PubMedGoogle Scholar
  6. 6.
    Keeler, R.F., and W. Binns, Proc. Soc. Exp. Biol. Med. 116:123 (1964).PubMedGoogle Scholar
  7. 7.
    Kupchan, S.M., J.H. Zimmerman, and A.A. Afonso, Lloydia 24:1 (1961).Google Scholar
  8. 8.
    Burroni, M., Caryologia 7:87 (1955).Google Scholar
  9. 9.
    Smith, D.L., and L.D. Hiner, J. Am. Pharm. Assoc. 49:538 (1960).Google Scholar
  10. 10.
    Frank, H., Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg., Abt. 2, 113:128 (1959).Google Scholar
  11. 11.
    Keeler, R.F., and W. Binns, Can. J. Biochem. 44:819 (1966).PubMedCrossRefGoogle Scholar
  12. 12.
    Keeler, R.F., and W. Binns, Can. J. Biochem. 44:829 (1966).PubMedCrossRefGoogle Scholar
  13. 13.
    Keeler, R.F., and W. Binns, Teratology 1:5 (1968).PubMedCrossRefGoogle Scholar
  14. 14.
    Masamune, T., Y. Mori, M. Takasugi, and A. Murai, Tetrahedron Lett. 16:913 (1964).CrossRefGoogle Scholar
  15. 15.
    Keeler, R.F., Phytochemistry 8:223 (1969).CrossRefGoogle Scholar
  16. 16.
    Budzikiewicz, H., C. Djerassi, and D.H. Williams, in “Structural Elucidation of Natural Products by Mass Spectrometry,” Vol. II Holden Day, San Francisco, 1964 p. 21.Google Scholar
  17. 17.
    Keeler, R.F., Steroids 13:579 (1969).PubMedCrossRefGoogle Scholar
  18. 18.
    Binns, W., R.F. Keeler, and L.D. Balls, Clin. Toxicol. 5:245 (1972).PubMedCrossRefGoogle Scholar
  19. 19.
    Keeler, R.F., Teratology 3:175 (1970).PubMedCrossRefGoogle Scholar
  20. 20.
    Keeler, R.F., Proc. Soc. Exp. Biol. Med. 136:1174 (1971).PubMedGoogle Scholar
  21. 21.
    Keeler, R.F., Proc. Soc. Exp. Biol. Med. 149:302 (1975).PubMedGoogle Scholar
  22. 22.
    Bryden, M.M., C. Perry, and R.F. Keeler, Teratology 8:19 (1973).PubMedCrossRefGoogle Scholar
  23. 23.
    Bryden, M.M., and R.F. Keeler, J. Anat. 116:464 (1974).Google Scholar
  24. 24.
    Keeler, R.F., Proc. Soc. Exp. Biol. Med. 142:1287 (1973).PubMedGoogle Scholar
  25. 25.
    Schreiber, K., “Steroidal Alkaloids: The Solanum Group,” in “The Alkaloids”, Vol. X, Edited by R.H.F. Manske, Academic Press, New York, 1968, p. 1.Google Scholar
  26. 26.
    Keeler, R.F., Teratology 3:169 (1970).PubMedCrossRefGoogle Scholar
  27. 27.
    Keeler, R.F., Steroids 18:741 (1971).PubMedCrossRefGoogle Scholar
  28. 28.
    Renwick, J.H., J. Prev. Soc. Med. 26:67 (1972).Google Scholar
  29. 29.
    Lemire, R.J., J.B. Beckwith, and J. Warkany, in “Anencephalus,” Raven Press, New York, 1978, p. 25.Google Scholar
  30. 30.
    Keeler, R.F., Lancet 1:1187 (1973).PubMedCrossRefGoogle Scholar
  31. 31.
    Keeler, R.F., S. Young, and D. Brown, Res. Commun. Chem. Pathol. Pharmacol. 13:723 (1976).PubMedGoogle Scholar
  32. 32.
    Seifulla, Kh. I., and K.E. Ryzhova, Chem. Abstr. 83:22383 (1975).Google Scholar
  33. 33.
    Brown, D., and R.F. Keeler, J. Agric. Food Chem. 26:561, 564, 566 (1978).PubMedCrossRefGoogle Scholar
  34. 34.
    Keeler, R.F., D.R. Douglas, and G.F. Stallknecht, Am. Potato J. 52:125 (1975).Google Scholar
  35. 35.
    Keeler, R.F., D. Brown, D.R. Douglas, G.F. Stallknecht, and S. Young, Bull. Environ. contam. Toxicol. 15:522 (1976).PubMedCrossRefGoogle Scholar
  36. 36.
    Keeler, R.F., S. Young, D. Brown, G.F. Stallknecht, and D. Douglas, Teratology 178:327 (1978).CrossRefGoogle Scholar

Copyright information

© American Oil Chemists’ Society 1978

Authors and Affiliations

  • Richard F. Keeler
    • 1
  1. 1.Science and Education Administration, Poisonous Plant Research LaboratoryU.S. Department of AgricultureLogan

Personalised recommendations