Abstract
5 alpha-Cholest-8(14)-en-3 beta-ol-15-one is a very potent inhibitor of sterol biosynthesis in animal cells in culture (G. J. Schroepfer, Jr., E. J. Parish, H. W. Chen, and A. A. Kandutsch (1977) J. Biol. Chem. 252, 8975-8980) and has significant hypocholesterolemic activity upon dietary administration to normal animals (G. J. Schroepfer, Jr., D. Monger, A. S. Taylor, J. S. Chamberlain, E. J. Parish, A. Kisic, and A. A. Kandutsch (1977) Biochem. Biophys. Res. Commun. 78, 1227-1233). In the present study we have prepared [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one by chemical synthesis. This compound has been shown to be convertible to cholesterol upon incubation with the 10,000 X g supernatant fraction of rat liver homogenates under aerobic conditions. The efficiency of this conversion was higher in preparations derived from male rats than in those obtained from female rats. Labeled 5 alpha-cholest-7-en-3 beta-ol was also isolated and characterized as a product of the metabolism of the labeled delta 8(14)-15-ketosterol. The demonstration of the enzymatic conversion of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one to cholesterol in liver preparations suggests that previous estimates of the biological potency of this compound may be much lower than the true values and/or that metabolites of this compound may be the active species responsible for its biological actions.
Highlights
Theresultspresentedherein clearlyestablish that [2,4~’H]5a-cholest-8(14)-en-3~-ol-15p-roenpea,red by chemical synthesis (Fig. IO), is convertible to cholesterol upon incubation with rat liver homogenate preparations (10,000 X g supernatant fraction supplemented with NAD, NADP, andglucose 6-phosphate) under aerobic conditions
5a-Cholest-8(14)-en-3~-01-15-on(eFig. 1) has been found to en-3P-ol-15-one is in contrast with the resultsof studies of the be a potent inhibitor of sterol biosynthesis in animal cells in metabolism of another 15-oxygenated sterol, 5a,14P-cholest-7
We have previously investigated the metabolism of the two 15-hydroxy epimers of the A8c14’-15-ketosteroiln rat liver homogenate preparations and inmicrosomes derived therefrom [14, 20, 43]
Summary
Theresultspresentedherein clearlyestablish that [2,4~’H]5a-cholest-8(14)-en-3~-ol-15p-roenpea,red by chemical synthesis (Fig. IO), is convertible to cholesterol upon incubation with rat liver homogenate preparations (10,000 X g supernatant fraction supplemented with NAD, NADP, andglucose 6-phosphate) under aerobic conditions. The extents of the been shown to be convertible to cholesterol upon in- incorporation of [2,4-”H]5a-cholest-8(14)-en-3,8-01-15-oneinto cubation with the 10,000 X g supernatant fraction of rat cholesterol inthese homogenate preparations asruemmarized liver homogenates under aerobic conditions.
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