Inhibition of sterol synthesis and reduction of HMG - CoA reductase activity in L cells by derivatives of 14 a - ethyl - 5 a - cholest

Reported herein are the results of investigations of the effects of a number of 14a-alkyl-substituted 15oxygenated sterols, prepared by chemical synthesis, on sterol biosynthesis and the levels of 3-hydroxy-3-methylglutaryl CoA reductase activity in L cells and in primary cultures of fetal mouse liver cells grown in serum-free media. Several of the compounds, most notably 14a-ethyl5a-cholest-7-en-3/3,15a-diol and 14a-ethyl-5a-cholest-7-en15a-ol-3-one, were found to be extraordinarily potent inhibitors of sterol synthesis in these cells. For example, the latter compound caused a 50% inhibition of the incorporation of labeled acetate into digitonin-precipitable sterols in L cells in culture at a concentration of 6 x lo-’ M. --Schroepfer, G. J., Jr., E. J. Parish, M. Tsuda, D. L. Raulston, and A. A. Kandutsch. Inhibition of sterol biosynthesis in animal cells by 14a-alkyl-substituted 15oxygenated stero1s.J. Lipid Res. 1979. 20: 994-998. Supplementary key words HMG-CoA reductase mouse L cells * fetal mouse liver cells . A number of oxygenated derivatives of cholesterol and related sterols have been shown to act as potent inhibitors of sterol biosynthesis in animal cells in culture (1 12). Recently we have found that a number of 15-oxygenated sterols serve as very potent inhibitors of sterol synthesis in animal cells (812). One of the more potent inhibitors of this type, identified in initial studies, was 14a-methyl-5a-cholest-7-en3&15a-diol which caused a 50% inhibition of sterol synthesis in L cells and in primary cultures of liver cells at 3.0 x M and 1.8 x low6 M, respectively (9). The same sterol resulted in a 50% reduction of the activity of HMG-CoA reductase in the L cells and in the mouse liver cells at concentrations of 3.0 x M and 2.0 x As an extension of our initial studies of 15-oxygenated sterols as inhibitors of sterol synthesis, we have investigated the effects of additional 14aalkyl substituted 15-oxygenated sterols and their derivatives on sterol synthesis in L cells and fetal mouse liver cells grown in serum-free media. A number of the new compounds studied have been found to be M, respectively (9). extraordinarily active in the inhibition of sterol synthesis. Preliminary accounts of portions of this research have been published (10, 11). EXPERIMENTAL PROCEDURE