MECHANISM OF ACTION OF MER-29, AN INHIBITOR OF CHOLESTEROL BIOSYNTHESIS
MECHANISM OF ACTION OF MER-29, AN INHIBITOR OF CHOLESTEROL BIOSYNTHESIS
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DOI：
10.1016/0006-291x(60)90266-7
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发表时间：
1960-01-01
影响因子：
3.1
通讯作者：
MOSETTIG, E
中科院分区：
文献类型：
--
作者：
AVIGAN, J;STEINBERG, D;MOSETTIG, E
麦肯齐和Blohm（1959）已经表明，对大鼠施用MER-29（1-（对甲苯基）-2-（对氯苯基）乙醇）导致胆固醇生物合成速率的显著抑制以及血清和组织胆固醇水平的降低。他们的研究（在本实验室中得到证实）表明，在接受MER-29的大鼠中，C14-乙酸盐放射性掺入总不可皂化脂质部分和肝脏洋地黄皂苷可沉淀部分中的情况与对照大鼠中观察到的情况相当。然而，当通过二溴化物纯化从洋地黄苷中提取的胆固醇时，发现实际上很少的掺入的放射性是胆固醇本身，大部分放射性保留在上清液中。目前的研究表明，在饮食中接受MER-29的大鼠的肝脏和血清中存在24-脱氢胆固醇（桥甾醇）的积累。这种甾醇被认为是胆固醇生物合成的中间体，最近Stokes及其同事（19%）证明，注射到大鼠体内的标记24脱氢胆固醇可迅速转化为胆固醇。我们在喂食MER-29的大鼠中进行的示踪剂研究与24-溴代-24-羟基苯甲酸酯之间的示踪剂-产物关系一致。
MacKenzie and Blohm (1959) have shown that administration of MER-29 (l-~~-(~-diet~ lamlnoetho~)-phenyl~-l-(p-tolyl)-2-(pc~ orophenyl) ethanol) to rats leads to a marked depression of the rate of cholesterol biosynthesis and to a decrease in serum and tissue levels of cholesterol. Their studies, confirmed in this laboratory, showed that the incorporation of C 14-acetate radioactivity into the total nonsaponifiable lipid fraction and into the digitonin-precipitable fraction of the liver in rats receiving MER-29 was comparable to that observed in control rats. However, when the cholesterol Aiberated from the digitonide was purified through the dibromide, it was found that actually very little of the incorporated radioactivity was in cholesterol itself, most of the radioactivity remaining in the supernatant solution.The present studies show that there is an accumulation of 24-dehydrocholesterol (desmosteroi) in the liver and in the serum of rats receiving MER-29 in the diet. This sterol has been postulated as an intermediate in cholesterol biosynthesis and it has recently been shown by Stokes and coworkers (19%) that labeled 24rdehydrocholesterol injected into rats is rapidly converted to cholesterol. Our tracer studies in rats fed MER-29 are compatible with a precursor-product relationship between 24-dehydro-