Abstract
Ketoconazole, an antimycotic agent, given to rats for a week as 0.05% food addition had no effect on the hepatic concentrations of free and esterified cholesterol or on the activity of acyl coenzyme A: cholesterol-acyltransferase (ACAT). However, the levels of free methylated cholesterol precursors, especially lanosterols, less markedly Δ8,24 and Δ8-dimethyl sterols and monomethyl sterols, were increased after only one day's treatment, while those of esterified methyl sterols were increased inconsistently, and those of free and esterified Δ8-lathosterol, lathosterol and desmosterol were not affected at all. Cholestyramine treatment had no significant effect on ACAT in spite of a decrease in the hepatic content of esterified cholesterol and caused a marked increase in the free cholesterol precursor levels, especially in those of lathosterols. Cholestyramine given to ketoconazole-treated rats increased the hepatic levels of Δ8 and Δ7-lathosterols but not desmosterol or methylated cholesterol precursors. Ketoconazole increased and cholestyramine markedly decreased plantssterols, sitosterol and campesterol in the liver. In serum, the contents of both lanosterols and lathosterol were increased but that of cholesterol tended to be decreased by ketoconazole (−19%). The results indicate that ketoconazole impairs demethylation processes at C-14 and to some extent at C-4 in the rat liver, resulting in lowered serum cholesterol level.
Similar content being viewed by others
Abbreviations
- ACAT:
-
acyl coenzyme A: cholesterol acyltransferase; campesterol (5α-cholest-24χ-methyl-3β-ol); cholesterol (cholest-5-en-3β-ol), desmosterol (5α-cholest-5,24-dien-3β-ol)
- DHL:
-
dihydrolanosterol (4,4,14α-trimethyl-5α-cholest-8-en-3β-ol)
- Δ8,24 DMS (4,4-dimethyl-5α-cholest-8(7):
-
24-dien-3-β-ol); Δ8DMS (4,4-dimethyl-5-α-cholest-8-en-3β-ol)
- GLC:
-
gas liquid chromatography
- HMG-CoA:
-
hydroxymethyl-glutaryl coenzyme A
- lanosterol:
-
(4,4,14α-trimethyl-5α-cholest-8,24-dien-3β-ol)
- Δ8lathosterol:
-
(5α-cholest-8-en-3β-ol)
- lathosterol:
-
(5α-cholest-7-en-3β-ol)
- Δ8methostenol:
-
(4α-methyl-5α-cholest-8-en-3β-ol); methostenol (4α-methyl-5α-cholest-7-en-3β-ol)
- sitosterol:
-
(5α-cholest-24χ-ethyl-3β-ol)
- Δ5,7-cholestenol:
-
(cholesta-5,7-dien-3β-ol)
- TLC:
-
thin layer chromatography
References
Grayhill, J.R., and Drutz, D.J. (1980)Ann. Intern. Med. 93, 921–923.
Cools, W., Cornelissen, F., Lauwers, W., and van Cutsen, J.M. (1980)Antimicrob. Agents. Chemother. 17, 922–928
Bloch, K. (1979)Crit. Rev. Biochem. 7, 1–5.
Pont, A., Williams, P.L., Azhar, S., Reitz, S., Reitz, R.E., Bochra, C., Smith, E.R., and Stevens, D.A. (1982)Arch. Intern. Med. 142, 2137–2140.
Pont, A., Williams, P.L., Loose, D.S., Feldman, D., Reitz, R.E., Bochra, C., and Stevens, D.A. (1982)Ann. Intern. Med. 97, 370–372.
Trachtenberg, T., and Pont, A. (1984)Lancet ii, 433–435.
Miettinen, T.A., and Valtonen, V.V. (1984)Lancet ii, 1271.
Folch, J., Lees M., and Sloane-Stanley, G.H. (1957)J. Biol. Chem. 226, 497–509.
Miettinen, T.A., and Koivisto, P. (1983) inBile Acids and Cholesterol in Health and Disease (Paumgartner, G., Stiehl, A., and Gerok, W., eds.) pp. 183–187, MTP Press, Boston, MA.
Tilvis, R.S., and Miettinen, T.A. (1980)Arch. Pathol. Lab. Med. 104, 35–40.
Myant, N.B. (1981) inThe Biology of Cholesterol and Related Sterols, pp. 207–213, William Heinemann Medical Books Ltd, London.
Erickson, S.K., Shrewsbury, M.A., Brooks, C., and Meyer, D.J. (1980)J. Lipid Res. 21, 930–941.
Lowry, O.H., Rosenbrough, N.J., Farr A.L., and Randall, R.J. (1951)J. Biol. Chem. 193, 265–275
Miettinen, T.A., Kesäniemi, Y.A., Färkkilä, M., Koivisto, P., and Vuoristo, M. (1987)Am. Heart J. 113, 487–493.
Gaylor, J.L., and Mason, H.S. (1968)J. Biol. Chem. 243, 4966–4972.
Yamaga, N., and Gaylor, J.L. (1978)J. Lipid Res. 19, 375–382.
Loose, D.S., Kam, P.B., Hirst, M.A., Marcus, R.A., and Feldman, D. (1983)J. Clin. Invest. 71, 1495–1499.
Salen, G., Ahrens, E.H. Jr., and Grundy, S.M. (1970)J. Clin. Invest. 49, G52-G67
Princen, H.M.G., Huijsmans, C.M.G., Kuipers, F., Vonk, R.J., and Kempen, H.J.M. (1986)J. Clin. Invest. 78, 1064–1071.
Spence, J.T., and Gaylor, J.L. (1977)J. Biol. Chem. 252, 5852–5858.
Miettinen, T.A. (1969)Life Sci. 8, 713–721.
Tavani, D.M., Nes, W.R., and Billheimer, J.T. (1982),J. Lipid Res. 23, 774–781.
Author information
Authors and Affiliations
About this article
Cite this article
Strandberg, T.E., Tilvis, R.S. & Miettinen, T.A. Effects of ketoconazole on cholesterol synthesis and precursor concentrations in the rat liver. Lipids 22, 1020–1024 (1987). https://doi.org/10.1007/BF02536443
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02536443