Monger D J, Schroepfer G J
Department of Biochemistry, Rice University, Houston, TX 77251.
Chem Phys Lipids. 1988 May;47(1):21-46. doi: 10.1016/0009-3084(88)90030-8.
5 alpha-Cholest-8(14)-en-3 beta-ol-15-one is a potent inhibitor of sterol biosynthesis in mammalian cells in culture and has significant hypocholesterolemic activity upon oral administration to rodents and non-human primates. The conversion of the 15-ketosterol to cholesterol upon incubation with the 10,000 x g supernatant fraction of rat liver homogenate preparations under aerobic conditions has been reported (D.J. Monger, E.J. Parish and G.J. Schroepfer, Jr. (1980) J. Biol. Chem. 255, 11122-11129). Presented herein are results of studies of the metabolism of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one obtained upon incubation with the microsomal, cytosolic and the 10,000 x g supernatant fractions of liver homogenates of female rats under a variety of conditions. The results of these studies indicated metabolism of the 15-ketosterol to materials with the chromatographic properties of fatty acid esters of the 15-ketosterol, fatty acid esters of C27-monohydroxysterols, a component similar to the 15-ketosterol (possibly an isomer of the delta 8(14)-15-ketosterol), and a polar component. Detailed studies of the C27-monohydroxysterols obtained from incubation of the 15-ketosterol under anaerobic conditions indicated the formation of labeled 5 alpha-cholesta-8,14-dien-3 beta-ol and 5 alpha-cholest-7-en-3 beta-ol which were characterized by their behavior on silicic acid column chromatography, by the behavior of their acetate derivatives on medium pressure liquid chromatography on alumina-AgNO3 columns, and by co-crystallization of the labeled sterols with authentic unlabeled standards. The identification of 5 alpha-cholesta-8,14-dien-3 beta-ol and 5 alpha-cholest-7-en-3 beta-ol as metabolites of the 15-ketesterol, coupled with previous studies of the metabolism of 5 alpha-cholesta-8,14-dien-3 beta-ol and of 5 alpha-cholest-8(14)-ene-3 beta, 15 alpha-diol and 5 alpha-cholest-8(14)-ene-3 beta, 15 beta-diol has permitted the formulation of a scheme for the overall metabolism of the 15-ketosterol to cholesterol.
5α-胆甾-8(14)-烯-3β-醇-15-酮是培养的哺乳动物细胞中甾醇生物合成的有效抑制剂，对啮齿动物和非人类灵长类动物口服给药后具有显著的降胆固醇活性。据报道，在有氧条件下，将15-酮甾醇与大鼠肝脏匀浆制剂的10000×g上清液部分一起孵育时，可将其转化为胆固醇（D.J. Monger、E.J. Parish和G.J. Schroepfer, Jr.（1980年）《生物化学杂志》255卷，11122 - 11129页）。本文介绍了在各种条件下，将[2,4-³H]5α-胆甾-8(14)-烯-3β-醇-15-酮与雌性大鼠肝脏匀浆的微粒体、胞质溶胶和10000×g上清液部分一起孵育后得到的代谢研究结果。这些研究结果表明，15-酮甾醇代谢为具有15-酮甾醇脂肪酸酯、C27-单羟基甾醇脂肪酸酯、一种类似于15-酮甾醇的成分（可能是δ8(14)-15-酮甾醇的异构体）和一种极性成分色谱性质的物质。对在厌氧条件下孵育15-酮甾醇得到的C27-单羟基甾醇的详细研究表明，形成了标记的5α-胆甾-8,14-二烯-3β-醇和5α-胆甾-7-烯-3β-醇，它们通过在硅酸柱色谱上的行为、其乙酸酯衍生物在氧化铝-硝酸银柱上的中压液相色谱行为以及标记甾醇与真实未标记标准品的共结晶来表征。将5α-胆甾-8,14-二烯-3β-醇和5α-胆甾-7-烯-3β-醇鉴定为15-酮甾醇的代谢产物，再结合先前对
