Schroepfer G J, Christophe A, Chu A J, Izumi A, Kisic A, Sherrill B C
Department of Biochemistry, Rice University, Houston, Texas.
Chem Phys Lipids. 1988 Sep;48(1-2):29-58. doi: 10.1016/0009-3084(88)90131-4.
The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one (I), a potent regulator of cholesterol (Chol) metabolism which has significant hypocholesterolemic activity upon oral administration to animals, has been investigated in male rats. After intragastric administration of [2,4-3H] I and [4-14C]Chol in triolein to intestinal lymph duct-cannulated rats, most of the 3H of the lymph was associated with chylomicrons. Most of the 3H in the chylomicrons was associated with fatty acid esters of I and the oleate ester represented the major species of the esters of I. After intravenous injection of the isolated doubly-labeled chylomicrons to intact rats, rapid clearance of 3H and 14C from blood was observed which was associated with a rapid and selective uptake of 3H and 14C by liver. The rate of disappearance of 3H from blood and the rate of uptake of 3H by liver were similar, if not identical, to those for 14C. In contrast, the disappearance of 3H from the liver was much more rapid than that of 14C. Studies of the distribution of 3H in liver demonstrated rapid formation of free I and the formation of [3H]Chol. In addition, significant amounts of the 3H in liver were associated with polar materials, a finding which was not observed in the case of 14C. After intravenous administration of the doubly-labeled chylomicrons to bile duct-cannulated rats, very rapid and substantial metabolism of the administered 3H to polar biliary metabolites was observed. The bulk of the 3H not recovered in bile at 49 h after the injection of the labeled chylomicrons was recovered in blood and tissues and almost all (integral of 94%) of this material was associated with Chol and Chol esters. The combined results indicate an important role for chylomicrons in the overall metabolism of I. The selective delivery of I to liver as its oleate ester in chylomicrons (or, more probably, as chylomicron remnants) and the subsequent metabolism of the oleate ester of I in liver has important consequences with respect to the actions of I which are discussed herein.
5α-胆甾-8(14)-烯-3β-醇-15-酮（I）是胆固醇（Chol）代谢的一种强效调节剂，对动物口服给药时具有显著的降胆固醇活性。本文对其在雄性大鼠体内的代谢进行了研究。向肠道淋巴管插管的大鼠胃内给予[2,4-³H]I和溶于三油酸甘油酯的[4-¹⁴C]Chol后，淋巴液中的大部分³H与乳糜微粒相关。乳糜微粒中的大部分³H与I的脂肪酸酯相关，油酸酯是I酯的主要种类。将分离的双标记乳糜微粒静脉注射给完整大鼠后，观察到³H和¹⁴C从血液中迅速清除，这与肝脏对³H和¹⁴C的快速选择性摄取有关。³H从血液中的消失速率和肝脏对³H的摄取速率与¹⁴C的相似，甚至相同。相比之下，³H从肝脏中的消失比¹⁴C快得多。肝脏中³H分布的研究表明，游离I迅速形成，同时形成了[³H]Chol。此外，肝脏中大量的³H与极性物质相关，¹⁴C的情况则未观察到这一现象。向胆管插管的大鼠静脉注射双标记乳糜微粒后，观察到所给予的³H迅速大量代谢为极性胆汁代谢物。注射标记乳糜微粒49小时后，未在胆汁中回收的大部分³H在血液和组织中被回收，并且几乎所有（94%的积分）这种物质都与Chol和Chol酯相关。综合结果表明乳糜微粒在I的整体代谢中起重要作用。I以其油酸酯的形式（或者更可能是以乳糜微粒残粒的形式）在乳糜微粒中选择性地输送到肝脏，随后I的油酸酯在肝脏中的代谢对于I的作用具有重要影响，本文对此进行了讨论。
