cholest-8(14)-en-3-ol-15-one and Body-Weight

The 7 alpha-methyl analog (II) of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15- one (I) was prepared by chemical synthesis and evaluated with respect to its effects on HMG-CoA reductase activity in CHO-K1 cells and on serum cholesterol levels in rats. The 7 alpha-methyl substitution had no detectable effect on the potency of I in lowering HMG-CoA reductase activity in the cultured cells. In contrast, the 7 alpha-methyl substitution had a marked effect on the action of I in the suppression of food consumption in rats. Whereas II was less potent than I in lowering serum cholesterol levels in rats, it did so at dosage levels at which only slight or moderate effects on food consumption were observed. Full 1H and 13C-NMR assignments for II and intermediates in its synthesis have been presented. Conformational analysis, based on 1H-1H coupling constants, NMR shieldings and force-field calculations, indicated that the 7 alpha-methyl substitution had virtually no effect on the conformation of the 15-ketosterol apart from minor distortions of ring B.

Topics: Animals; Body Weight; Cells, Cultured; CHO Cells; Cholestenones; Cholesterol; Cricetinae; Eating; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley; Sterols; Structure-Activity Relationship

3 beta-Hydroxy-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (VII), an analog of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I) in which conversion to 26- and 25-oxygenated metabolites is blocked by the F7-substitution, was administered to male Sprague-Dawley rats at levels of from 0.025 to 0.15% by weight in a ground chow diet. Administration of VII resulted in lowering of the levels of serum cholesterol at dosages as low as 0.025% by weight in diet. In marked contrast to I, VII had little or no effect on food consumption. Whereas administration of I at a level of 0.1% by weight in diet resulted in a cessation of growth, VII, at approximately the same molar concentration in diet, had only slight or no effect on changes in total body weight. Significant levels of 25,26,26,26,27,27,27-heptafluorocholesterol (VIII) were observed in serum and liver, indicating the conversion of VII to VIII. Characterization of VIII in liver was based upon the results of gas chromatography, low and high resolution mass spectral studies, infrared spectroscopy, and 1H and 13C nuclear magnetic resonance spectroscopy. The levels of VIII in serum appeared to be related to dosage and duration of administration of VII.

Topics: Animals; Body Weight; Cholestenones; Cholesterol; Chromatography, High Pressure Liquid; Colorimetry; Diet; Eating; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley; Sterols

The morphological effects of short-term (9 days) dietary administration (0.1% in a laboratory chow diet) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a novel regulator of cholesterol metabolism with significant hypocholesterolemic activity, has been studied in young male rats. Control animals included rats fed the basal diet ad libitum and a series of rats pair-fed to the individual experimental animals. At the time of necropsy, the morphological changes in rats which have been observed in rats following treatment with other absorbable hypolipidemic agents (myeloid bodies with triparanol, increased peroxisomes with clofibrate, and proliferation of smooth endoplasmic reticulum with compactin and mevinolin) were not apparent on ultrastructural examination of livers of rats treated with the 15-ketosterol. Two changes were observed in the rats fed the 15-ketosterol: a decrease in adipose tissue and enlargement of the small intestine. Diminished fat was also noted in the pair-fed controls and was presumably due to decreased food consumption. The intestines of rats fed the 15-ketosterol were morphometrically most enlarged in the jejunal region. Morphologically, this increase was distinguished by increased depth of crypts of Lieberkuhn and pseudostratification of epithelium at the base of the villi. These changes were qualitatively and quantitatively similar to the adaptive changes reported in the rat after resection of small bowel or following intestinal bypass (segment of bowel remaining in continuity). The morphological changes induced in the rat by administration of the 15-ketosterol were not observed in 4 baboons which received the compound orally at doses of 50, 75, or 100 mg per kilogram of body weight for up to 3 months.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholestenes; Cholestenones; Cholesterol; Diet; Eating; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Inbred Strains; Time Factors

The effects of dietary administration (0.1% in diet for 8 days) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one on the levels of activity of cytosolic acetoacetyl coenzyme A thiolase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, and microsomal HMG-CoA reductase in liver have been studied in male Sprague-Dawley rats. Significant increases in the levels of activity of acetoacetyl-CoA thiolase and of HMG-CoA synthase were observed. The levels of microsomal HMG-CoA reductase activity were increased, relative to pair-fed control animals, in three experiments and increased, relative to ad libitum control animals, in one of three experiments. When compared with other agents for which the primary mode of action is an inhibition of the intestinal absorption of cholesterol, the magnitude of the increases in the levels of hepatic microsomal HMG-CoA reductase activity in the 15-ketosterol-fed rats was considerably smaller. In view of the previously described marked activity of the 15-ketosterol in the inhibition of the intestinal absorption of cholesterol, as well as its known effects in lowering HMG-CoA reductase activity in mammalian cells in culture, it is proposed that the 15-ketosterol may suppress the elevated levels of hepatic microsomal HMG-CoA reductase activity induced by the reduced delivery of cholesterol to liver as a consequence of the inhibition of the intestinal absorption of cholesterol.

Topics: Acetyl-CoA C-Acetyltransferase; Animals; Anticholesteremic Agents; Body Weight; Cholestenes; Cholestenones; Cholesterol; Dietary Fats; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Synthase; Liver; Male; Microsomes, Liver; Rats; Rats, Inbred Strains

The effect of dietary administration (0.1% in a rat chow diet) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol biosynthesis with marked hypocholesterolemic activity, on the fate of [4-14C]cholesterol and [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one has been studied after intragastric administration of the labeled sterols to rats. In general, the distribution of 3H in major tissues paralleled that of 14C with no unusual concentration of 3H in any of the organs. Only trace amounts of 3H and 14C were recovered in urine. Administration of the 15-ketosterol was associated with decreased absorption of the labeled cholesterol as indicated by decreased levels of 14C in the various tissues and organs of the 15-ketosterol-treated rats (relative to ad libitum and pair-fed control animals) and increased levels of 14C in feces and intestinal contents at 12 and 48 h after the administration of the labeled cholesterol. Studies of the distribution of 3H in liver indicated rapid conversion of the 15-ketosterol to cholesterol and cholesteryl esters. The amounts of 3H recovered in the various tissues and organs at both 12 and 48 h after the administration of the labeled sterols were considerably less than the corresponding values for 14C, a finding which suggests a lower absorption of the 15-ketosterol (relative to cholesterol) and/or a more rapid clearance and biliary excretion of the 15-ketosterol and its metabolites.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholestenes; Cholestenones; Cholesterol; Dietary Fats; Male; Rats; Rats, Inbred Strains

The effect of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol synthesis with marked hypocholesterolemic activity, on the intestinal absorption of exogenous cholesterol has been studied in lymph-cannulated rats. Administration of the 15-ketosterol at a level of 0.05% in a rat chow diet for 10 days was associated with a marked decrease (-64%) in the absorption of cholesterol.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholestenes; Cholestenones; Cholesterol; Eating; Intestinal Absorption; Kinetics; Lymph; Male; Rats; Rats, Inbred Strains