Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1982 May;79(9):3042–3046. doi: 10.1073/pnas.79.9.3042

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of sterol biosynthesis, lowers serum cholesterol and alters distributions of cholesterol in lipoproteins in baboons.

G J Schroepfer Jr, E J Parish, A Kisic, E M Jackson, C M Farley, G E Mott
PMCID: PMC346345  PMID: 6953447

Abstract

5 alpha-Cholest-8(14)-en-3 beta-0l-15-one has been found to have significant hypocholesterolemic action on oral administration to baboons at dosages of 50 and 75 mg/kg of body weight. The 15-ketosterol decreased the levels of total serum cholesterol and low density lipoprotein plus very low density lipoprotein (LDL/VLDL) cholesterol and the percentage of total cholesterol associated with LDL/VLDL and increased the percentage of total cholesterol associated with high density lipoprotein (HDL). Moreover, administration of the steroid was associated with an absolute increase in the concentration of HDL cholesterol in those animals with low HDL levels (or with a low percentage of total serum cholesterol in the HDL fraction.

Full text

PDF
3042

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ABEL L. L., LEVY B. B., BRODIE B. B., KENDALL F. E. A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem. 1952 Mar;195(1):357–366. [PubMed] [Google Scholar]
  2. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  3. BARR D. P., RUSS E. M., EDER H. A. Protein-lipid relationships in human plasma. II. In atherosclerosis and related conditions. Am J Med. 1951 Oct;11(4):480–493. doi: 10.1016/0002-9343(51)90183-0. [DOI] [PubMed] [Google Scholar]
  4. BURSTEIN M., SAMAILLE J. [On a rapid determination of the cholesterol bound to the serum alpha- and beta-lipoproteins]. Clin Chim Acta. 1960 Jul;5:609–609. doi: 10.1016/0009-8981(60)90075-9. [DOI] [PubMed] [Google Scholar]
  5. Castelli W. P., Doyle J. T., Gordon T., Hames C. G., Hjortland M. C., Hulley S. B., Kagan A., Zukel W. J. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation. 1977 May;55(5):767–772. doi: 10.1161/01.cir.55.5.767. [DOI] [PubMed] [Google Scholar]
  6. Gofman J. W., Young W., Tandy R. Ischemic heart disease, atherosclerosis, and longevity. Circulation. 1966 Oct;34(4):679–697. doi: 10.1161/01.cir.34.4.679. [DOI] [PubMed] [Google Scholar]
  7. Gordon T., Castelli W. P., Hjortland M. C., Kannel W. B., Dawber T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707–714. doi: 10.1016/0002-9343(77)90874-9. [DOI] [PubMed] [Google Scholar]
  8. Gordon T., Kannel W. B., Castelli W. P., Dawber T. R. Lipoproteins, cardiovascular disease, and death. The Framingham study. Arch Intern Med. 1981 Aug;141(9):1128–1131. [PubMed] [Google Scholar]
  9. Huntoon S., Fourcans B., Lutsky B. N., Parish E. J., Emery H., Knapp F. F., Jr, Schroepfer G. J., Jr Sterol Synthesis. Chemical syntheses, spectral properties, and metabolism of 5alpha-cholest-8(14)-en-3beta,15beta-diol and 5alpha-cholest-8(14)-en-3beta,15alpha-diol. J Biol Chem. 1978 Feb 10;253(3):775–782. [PubMed] [Google Scholar]
  10. Kannel W. B., Castelli W. P., Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med. 1979 Jan;90(1):85–91. doi: 10.7326/0003-4819-90-1-85. [DOI] [PubMed] [Google Scholar]
  11. Knapp F. F., Jr, Schroepfer G. J., Jr Chemical synthesis, spectral properties, and chromatography of 4alpha-methyl and 4beta-methyl isomers of (24R)-24-ethyl-5alpha-cholestan-3beta-ol and (24S)-24-ethyl-cholesta-5,22-dien-3beta-ol. Steroids. 1975 Sep;26(3):339–357. doi: 10.1016/0039-128x(75)90079-3. [DOI] [PubMed] [Google Scholar]
  12. Levy R. I. Cholesterol, lipoproteins, apoproteins, and heart disease: present status and future prospects. Clin Chem. 1981 May;27(5):653–662. [PubMed] [Google Scholar]
  13. Mabuchi H., Haba T., Tatami R., Miyamoto S., Sakai Y., Wakasugi T., Watanabe A., Koizumi J., Takeda R. Effect of an inhibitor of 3-hydroxy-3-methyglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10-levels in patients with familial hypercholesterolemia. N Engl J Med. 1981 Aug 27;305(9):478–482. doi: 10.1056/NEJM198108273050902. [DOI] [PubMed] [Google Scholar]
  14. McGill H. C., Jr, McMahan C. A., Kruski A. W., Mott G. E. Relationship of lipoprotein cholesterol concentrations to experimental atherosclerosis in baboons. Arteriosclerosis. 1981 Jan-Feb;1(1):3–12. doi: 10.1161/01.atv.1.1.3. [DOI] [PubMed] [Google Scholar]
  15. Miller G. J. High density lipoproteins and atherosclerosis. Annu Rev Med. 1980;31:97–108. doi: 10.1146/annurev.me.31.020180.000525. [DOI] [PubMed] [Google Scholar]
  16. Miller L. R., Pajewski T. N., Schroepfer G. J., Jr Inhibitors of sterol synthesis. Studies of in vitro effects of C27 15-oxygenated sterols on sterol synthesis in cell free homogenates of rat liver. J Biol Chem. 1982 Mar 10;257(5):2412–2419. [PubMed] [Google Scholar]
  17. Miller L. R., Pascal R. A., Jr, Schroepfer G. J., Jr Inhibitors of sterol synthesis. Differential effects of 14 alpha-hydroxymethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol and 14 alpha-hydroxymethyl-5 alpha-cholest-6-ene-3 beta, 15 alpha-diol on sterol synthesis in cell-free homogenates of rat liver. J Biol Chem. 1981 Aug 10;256(15):8085–8091. [PubMed] [Google Scholar]
  18. Monger D. J., Parish E. J., Schroepfer G. J., Jr 15-Oxygenated sterols. Enzymatic conversion of [2,4]3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one to cholesterol in rat liver homogenate preparations. J Biol Chem. 1980 Dec 10;255(23):11122–11129. [PubMed] [Google Scholar]
  19. Parish E. J., Spike T. E., Schroepfer G. J., Jr Sterol synthesis. Chemical synthesis of 3beta-benzoyloxy -14alpha, 15alpha-epoxy-5alpha-cholest-7-ene, a key intermediate in the synthesis of 15-oxygenated sterols. Chem Phys Lipids. 1977 Apr;18(3-4):233–239. doi: 10.1016/0009-3084(77)90011-1. [DOI] [PubMed] [Google Scholar]
  20. Pinkerton F. D., Izumi A., Anderson C. M., Miller L. R., Kisic A., Schroepfer G. J., Jr 14 alpha-Ethyl-5 alpha-cholest-7-ene-3 beta,15 alpha-diol, a potent inhibitor of sterol biosynthesis, has two sites of action in cultured mammalian cells. J Biol Chem. 1982 Feb 25;257(4):1929–1936. [PubMed] [Google Scholar]
  21. SCHROEPFER G. J., Jr Lipid factors in atherosclerosis. N Engl J Med. 1957 Dec 19;257(25):1223–contd. doi: 10.1056/NEJM195712192572506. [DOI] [PubMed] [Google Scholar]
  22. Schroepfer G. J., Jr, Monger D., Taylor A. S., Chamberlain J. S., Parish E. J., Kisic A., Kandutsch A. A. Inhibitors of sterol synthesis. Hypocholesterolemic action of dietary 5alpha-cholest-8(14)-en-3beta-ol-15-one in rats and mice. Biochem Biophys Res Commun. 1977 Oct 24;78(4):1227–1233. doi: 10.1016/0006-291x(77)91424-3. [DOI] [PubMed] [Google Scholar]
  23. Schroepfer G. J., Jr, Parish E. J., Chen H. W., Kandutsch A. A. Inhibition of sterol biosynthesis in L cells and mouse liver cells by 15-oxygenated sterols. J Biol Chem. 1977 Dec 25;252(24):8975–8980. [PubMed] [Google Scholar]
  24. Schroepfer G. J., Jr, Parish E. J., Kandutsch A. A. Further studies on the inhibition of sterol biosynthesis in animal cells by 15-oxygenated sterols. Chem Phys Lipids. 1979 Nov;25(3):265–285. doi: 10.1016/0009-3084(79)90111-7. [DOI] [PubMed] [Google Scholar]
  25. Schroepfer G. J., Jr, Parish E. J., Pascal R. A., Jr, Kandutsch A. A. Inhibition of sterol biosynthesis in animal cells by 14 alpha-hydroxymethyl sterols. J Lipid Res. 1980 Jul;21(5):571–584. [PubMed] [Google Scholar]
  26. Schroepfer G. J., Jr, Pascal R. A., Jr, Kandutsch A. A. Inhibition of sterol synthesis in animal cells by 15-oxygenated sterols with the unnatural cis-C-D ring junction-"5alpha,14beta-cholest-7-en-15alpha-ol-3-one and 5alpha,14beta-cholest-7-en-15beta-ol-3-one. Biochem Pharmacol. 1979;28(2):249–252. doi: 10.1016/0006-2952(79)90511-2. [DOI] [PubMed] [Google Scholar]
  27. Schroepfer G. J., Jr, Raulston D. L., Kandutsch A. A. Inhibition of sterol synthesis in L cells by 14alpha-ethyl-5alpha-cholest-7-en-15alpha-ol-3-one at nanomolar concentrations. Biochem Biophys Res Commun. 1977 Nov 21;79(2):406–410. doi: 10.1016/0006-291x(77)90172-3. [DOI] [PubMed] [Google Scholar]
  28. Schroepfer G. J., Jr Sterol biosynthesis. Annu Rev Biochem. 1981;50:585–621. doi: 10.1146/annurev.bi.50.070181.003101. [DOI] [PubMed] [Google Scholar]
  29. Schroepfer G. J., Jr, Walker V., Parish E. J., Kisic A. Inhibitors of sterol synthesis. Hypocholesterolemic action of dietary 9 alpha-fluoro-5 alpha-cholest-8(14)-en-3 beta-ol-15-one. Biochem Biophys Res Commun. 1980 Apr 14;93(3):813–818. doi: 10.1016/0006-291x(80)91149-3. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES