Cytotoxicity of oxidation derivatives of cholesterol on cultured aortic smooth muscle cells and their effect on cholesterol biosynthesis.
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Aortic smooth muscle cell death is an important initial lesion of atherosclerosis. A number of autooxidation products of cholesterol which has been recognized recently has the capability of inducing rabbits' aortic smooth cell death in vitro. Twelve oxidation derivatives of cholesterol, available commercially, were dissolved in small amounts of ethanol, then added to the culture medium at levels not exceeding 0.8%. The medium contained 10% fetal calf's serum which served as an in situ vehicle for the sterols. The degrees of cytotoxicity were graded and measured as percentage of dying and dead cells in the cultures within 24 hr. 25-Hydroxycholesterol and cholesthan-3 beta, 5 alpha, 6 beta-triol, were the most toxic compounds among the sterols tested. When these oxidation derivatives of cholesterol were added to these cultured cells, they significantly depressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a regulatory enzyme of cholesterol biosynthesis (up to 83% inhibition by 25 hydroxycholesterol at a 3 microgram/ml concentration in culture medium) but the sequence of degree of inhibition was not exactly correlated with that of cytotoxicity. Various mechanisms are speculated. Purified cholesterol showed no cytotoxic effect and minimal inhibition of cholesterol biosynthesis. (+info)
Metabolism of bile alcohols, 24-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24-tetrol and 3 alpha,7 alpha,12 alpha-trihydroxy-26,27-dinor-5 beta-cholestan-24-one, in rats.
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24-Nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 3 alpha,7 alpha,12 alpha-trihydroxy-26,27-dinor-5 beta-cholestan-24-one were administered intraperitoneally to bile fistula rats, and the metabolites excreted in the bile were analyzed. No formation of bile acids from these bile alcohols was observed. 7 alpha,12 alpha,25-Trihydroxy-24-nor-5 beta-cholestane-3 alpha-O-(beta-D-glucopyranosid)uronic acid was identified as the only biliary metabolite of the 24-nor-5 beta-cholestanetetrol. The major metabolite of the trihydroxy-26,27-dinor-5 beta-cholestanone was 7 alpha,12 alpha-dihydroxy-24-oxo-26,27-dinor-5 beta-cholestane-3 alpha-O-(beta-D-glucopyranosid)uronic acid, and the minor metabolite was the glucurono conjugate of 26,27-dinor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 beta-tetrol. The results indicated that in rat liver these C25- and C26-bile alcohols, in contrast to C27-bile alcohols, were not converted into bile acids, and that the glucuronide production became necessary for hepatic elimination of the accumulated bile alcohols. (+info)
Sterol synthesis. Chemical synthesis of 5 alpha-cholest-7-en-3 beta, 14 alpha-diol.
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Reported herein is the chemical synthesis of 5 alpha-cholest-7-en-3 beta, 14 alpha-diol by mild Wolff-Kishner reduction of 3 beta-acetoxy-8 alpha, 14 alpha-epoxy-5 alpha-cholestan-7-one. The preparation of 5 alpha-cholest-7-en-14 alpha-ol-3-one from 5 alpha is also described. These compounds were fully characterized by the results of infrared, nuclear magnetic resonance, and high and low resolution mass spectral studies. (+info)