Skip to main content
SpringerLink
Log in

Inhibition of cholesterol synthesis by cyclopropylamine derivatives of squalene in human hepatoblastoma cells in culture

  • Article
  • Published:
Lipids

Abstract

Two squalene derivatives, trisnorsqualene cyclopropylamine and trisnorsqualeneN-methylcyclopropylamine, were synthesized and tested for inhibition of lanosterol and squalene epoxide formation from squalene in rat hepatic microsomes, and for the inhibition of cholesterol syntheses in human cultured hepatoblastoma (HepG2) cells. Trisnorsqualene cyclopropylamine inhibited [3H]-squalene conversion to [3H]squalene epoxide in microsomes (IC50=5.0 μM), indicating that this derivative inhibited squalene mono-oxygenase. Trisnorsqualenen-methylcyclopropylamine inhibited [3H]squalene conversion to [3H]lanosterol (IC50=12.0 μM) and caused [3H]-squalene epoxide to accumulate in microsomes, indicating that this derivative inhibited 2,3-oxidosqualene cyclase. Cholesterol biosynthesis from [14C]acetate in HepG2 cells was inhibited by both derivatives (IC50=1.0 μM for trisnorsqualene cyclopropylamine; IC50=0.5 μM for trisnorsqualeneN-methylcyclopropylamine). Cells incubated with trisnorsqualene cyclopropylamine accumulated [14C]squalene, while cells incubated with trisnorsqualeneN-methylcyclopropylamine accumulated [14C]squalene epoxide and [14C]squalene diepoxide. The concentration range of inhibitor which caused these intermediates to accumulate coincided with that which inhibited cholesterol synthesis. The results indicate that cyclopropylamine derivatives of squalene are effective inhibitors of cholesterol synthesis, and that substitutions at the nitrogen affect enzyme selectivity and thus the mechanism of action of the compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

FBS:

fetal bovine serum

HBSS:

Hanks buffered salt solution

HMG-CoA:

3-hydroxy-3-methylglutaryl-coenzyme A

HPLC:

high-performance liquid chromatography

LPDS:

lipoprotein-deficient bovine serum

MEM:

minimal essential medium

References

  1. Tobert, J.A., Bell, G.D., Birtwell, J., James, I., Kukovetz, W.R., Pryor, J.S., Buntinx, A., Holmes, I.B., Chao, Y.S., and Bolognese, J.A. (1982)J. Clin. Invest. 69, 913–919.

    Article  PubMed  CAS  Google Scholar 

  2. Alberts, A.W., Chen, J., Kuron, G., Hunt, V., Juff, J., Hoffman, C., Rothrock, J., Lopez, M., Joshua, H., Harris, E., Patchett, A., Monaghan, R., Currie, S., Stapley, E., Albers-Schoberg, G., Hensens, O., Hirshfield, J., Hoogsteen, K., Liesch, J., and Springer, J. (1980)Proc. Natl. Acad. Sci. USA 77, 3957–3961.

    Article  PubMed  CAS  Google Scholar 

  3. Duriatti, A., Bouvier-Navé, P., Benveniste, P., Schuber, F., Delprino, L., Balliano, G., and Cattel, L. (1985)Biochem. Pharmacol. 34, 2765–2785.

    Article  PubMed  CAS  Google Scholar 

  4. Cattel, L., Ceruti, M., Viola, F., Delprino, L., Balliano, G., Duriatti, A., and Bouvier-Navé, P. (1986)Lipids 21, 31–38.

    Article  PubMed  CAS  Google Scholar 

  5. Balliano, G., Viola, F., Ceruti, M., and Cattel, L. (1988)Biochim. Biophys. Acta 959, 9–19.

    PubMed  CAS  Google Scholar 

  6. Sen, S.E., and Prestwich, G.D. (1989)J. Am. Chem. Soc. 111, 1508–1510.

    Article  CAS  Google Scholar 

  7. Ceruti, M., Viola, F., Grosa, G., Balliano, G., Delprino, L., and Cattel, L. (1988)J. Chem. Res. (S),1, 18–19.

    Google Scholar 

  8. Sen, S.E., and Prestwich, G.D. (1989)J. Am. Chem. Soc. 111, 8761–8762.

    Article  CAS  Google Scholar 

  9. Panini, S.R., Sexton, R.C., and Rudney, H. (1984)J. Biol. Chem. 259, 7767–7771.

    PubMed  CAS  Google Scholar 

  10. Goldstein, J.L., and Brown, M.S. (1990)Nature 343, 425–430.

    Article  PubMed  CAS  Google Scholar 

  11. Saat, Y.A., and Bloch, K. (1976)J. Biol. Chem. 251, 5155–5160.

    PubMed  CAS  Google Scholar 

  12. Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. (1951)J. Biol. Chem. 193, 265–275.

    PubMed  CAS  Google Scholar 

  13. Tullman, R.H., and Hanzlik, R.P. (1984)Drug Metabol. Rev. 15, 1163–1182.

    CAS  Google Scholar 

  14. Narula, A., Rahier, A., Benveniste, P., and Schuber, F. (1981)J. Am. Chem. Soc. 103, 2408–2409.

    Article  CAS  Google Scholar 

  15. Taton, M., Benveniste, P., and Rahier, A. (1987)Pure & Appl. Chem. 59, 287–294.

    CAS  Google Scholar 

  16. Rahier, A., Bouvier, P., Cattel, L., Narula, A., and Benveniste, P. (1983)Biochem. Soc. Trans. 11, 537–543.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Marion Merrell Dow Research Institute, 2110 E. Galbraith Rd., 45215, Cincinnati, OH

    W. A. Van Sickle, M. R. Angelastro, P. Wilson, J. R. Cooper, A. Marquart & M. A. Flanagan

Authors
  1. W. A. Van Sickle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. R. Angelastro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. R. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Marquart
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. A. Flanagan
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Van Sickle, W.A., Angelastro, M.R., Wilson, P. et al. Inhibition of cholesterol synthesis by cyclopropylamine derivatives of squalene in human hepatoblastoma cells in culture. Lipids 27, 157–160 (1992). https://doi.org/10.1007/BF02536171

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02536171

Keywords

Search

Navigation