Abstract
Mevalonic acid is an important biochemical intermediate in cholesterol synthesis and other processes involved in cell replication. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the enzyme which catalyzes mevalonic acid synthesis. To determine whether a potent competitive inhibitor of this enzyme, the drug simvastatin, may have an adverse effect on enterocyte cell replication and cholesterol metabolism, small intestinal biopsies from nine hypercholesterolemic subjects were obtained before and during treatment with simvastatin as a lipid-lowering agent. Histologic review of biopsies in a blinded manner detected no change in ratio of villous length to crypt length or in mitotic index which might indicate altered cell replication. Similarly, no significant change in measured activity of HMG-CoA reductase activity was observed. In spite of the high exposure of jejunal mucosal cells to this potent competitive inhibitor of a key enzyme, no adverse effect on growth could be detected.
Similar content being viewed by others
Abbreviations
- HMG-CoA:
-
3-hydroxy-3-methylglutaryl coenzyme A
- LDL:
-
low density lipoprotein
References
Siperstein, M.D., and Fegan, V.M. (1966)J. Biol. Chem. 241, 602–609.
Linn, T.C. (1967)J. Biol. Chem. 242, 990–993.
Brown, M.S., and Goldstein, J.L. (1980)J. Lipid Res. 21, 505–517.
Siperstein, M.D. (1984)J. Lipid Res. 25, 1462–1468.
Larsson, O., Barrios, C., Latham, C., Ruiz, J., Zetterberg, A., Zickert, P., and Wejde, J. (1989)Cancer Res. 49, 5605–5610.
Quesney-Huneeus, V., Wiley, M.H., and Siperstein, M.D. (1979)Proc. Natl. Acad. Sci. USA 76, 5056–5060.
Kaneko, I., Hazama-Shimada, Y., and Endo, A. (1978)Eur. J. Biochem. 87, 313–321.
Brown, M.S., Faust, J.R., and Goldstein, J.L. (1978)J. Biol. Chem. 253, 1121–1128.
Tanaka, R.D., Edwards, P.A., Lan, S.F., Knoppel, E.M., and Fogelman, A.M. (1982)J. Lipid Res. 23, 1026–1031.
Stone, B.G., Evans, C.D., Prigge, W.F., Duane, W.C., and Gebhard, R.L. (1989)J. Lipid Res. 30, 1943–1952.
MacDonald, W.C., Trier, J.S., and Everett, N.B. (1965)Gastroenterology 46, 405–417.
Stange, E.F., Preclik, G., Schneider, A., Alavi, M., and Ditschuneit, H. (1981)Biochim. Biophys. Acta 663, 613–620.
Pietro, D.A., Alexander, S., Mantell, G., Staggers, J.E., Cook, T.J., and Simvastatin Multicenter Study Group II (1989)Am. J. Cardiol. 63, 682–686.
Stein, E., Kreisberg, R., Miller, V., Mantell, G., Washington, L., Shapiro, D.R., and Simvastatin Multicenter Study Group I (1990)Arch. Intern. Med. 150, 341–345.
Hoffman, W.F., Alberts, A.W., Anderson, P.S., Chen, J.S., Smith, R.L., and Willard, A.K. (1986)J. Med. Chem. 29, 849–852.
Duane, W.C., Hunninghake, D.B., Freeman, M.L., Pooler, P.A., Schlasner, L.A., and Gebhard, R.L. (1988)Hepatology 8, 1147–1150.
Freeman, M.L., Prigge, W.F., Hunninghake, D.B., Duane, W.C., and Gebhard, R.L. (1988)J. Lipid Res. 29, 839–845.
Yardley, J.H., Bayless, T.M., Norton, J.H., and Hendrix, T.R. (1962)N. Engl. J. Med. 267, 1173–1179.
Schenk, E.A., and Klipstein, F.A. (1972)Am. J. Clin. Nutr. 25, 1108–1117.
Vickers, S., Duncan, C.A., Chen, I.-W., Rosegray, A., and Duggan, D.E. (1990)Drug Metab. Disp. 18, 138–145.
Grieco, D., Beg, Z.H., Romano, A., Bifulco, M., and Aloj, S.M. (1990)J. Biol. Chem. 265, 19343–19350.
Singer, I.I., Kawka, D.W., McNally, S.E., Scott, S., Alberts, A.W., Chen, J.S., and Huff, J.W. (1987)Arteriosclerosis 7, 144–151.
Reihnér, E., Rudling, M., Ståhlberg, D., Berglund, L., Ewerth, S., Björkhem, I., Einarsson, K., and Angelin, B. (1990)N. Engl. J. Med. 323, 224–228.
Gebhard, R.L., Prigge, W.F., Andreini, J.P., and Freeman, M.L. (1991)J. Lab. Clin. Med. 117, 299–304.
Author information
Authors and Affiliations
About this article
Cite this article
Gebhard, R.L., Ewing, S.L., Schlasner, L.A. et al. Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition on human gut mucosa. Lipids 26, 492–494 (1991). https://doi.org/10.1007/BF02536591
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02536591