Mechanism of degradation of the steroid side chain in the formation of bile acids.
Mechanism of degradation of the steroid side chain in the formation of bile acids.
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发表时间：
1992-04
影响因子：
6.5
通讯作者：
Ingemar Björkhem
中科院分区：
文献类型：
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作者：
Ingemar Björkhem
哺乳动物中胆固醇代谢和排泄的最重要途径是胆汁酸的形成。两种主要的初级胆汁酸，胆酸和鹅去氧胆酸，在肝脏中形成并通过胆汁分泌到肠道。胆固醇转化为胆汁酸涉及将亲脂性化合物转化为可排泄的水溶性产物的几乎所有可能的机制（一般回顾，请参见参考文献 1）。在参与转化的超过 15 种不同酶中，羟化酶、氧化还原酶和缀合系统对于增加极性特别重要。修饰类固醇核的酶能够将非极性3~羟基A5-类固醇转化为极性更强的5~胆甾烷-αi~~,7~~-二羟基5p胆甾烷-Sa,7a,12a-三羟基类固醇。参与这些转化的酶主要位于内质网和细胞质中。参与类固醇侧链降解的酶将高度非极性的 Cp类固醇侧链转化为与氨基酸缀合的链缩短的羧酸。这些酶主要位于线粒体和过氧化物酶体中。根据目前的概念，哺乳动物中胆固醇转化为胆汁酸始于核转化，并且大部分或全部这些变化先于类固醇侧链的变化。根据对大鼠的早期体内和体外研究，大约 25 年前制定了图 1 所示的反应顺序，用于将胆固醇转化为胆酸和鹅去氧胆酸。然而，很明显，当类固醇侧链的部分或大部分变化先于细胞核的变化时，存在替代途径。由于胆汁酸的通量可能不会调节任何 7a-羟基化不是第一步的途径，因此胆固醇 7a-羟化酶似乎是唯一能够调节胆汁酸总体转化的酶。植物甾醇的甾体侧链在24位含有甲基或乙基。这意味着侧链降解的正常机制无法发挥作用。鉴于这些类固醇的吸收程度非常低，因此不需要专门的降解酶。然而，在至少一种哺乳动物物种中，已经进化出一种能够将植物甾醇转化为高极性共轭CnI-胆汁酸的系统。在本综述中，重点是与胆汁酸生物合成相关的类固醇侧链降解的最重要机制，27-
The most important pathway for the metabolism and excretion of cholesterol in mammals is the formation of bile acids. The two major primary bile acids, cholic and chenodeoxycholic acids, are formed in the liver and secreted in bile to the intestine. The conversion of cholesterol into bile acids involves almost all the conceivable mechanisms for conversion of a lipophilic compound into an excretable water-soluble product (for a general review, see ref. 1). Of the more than 15 different enzymes participating in the conversion, hydroxylases, oxidoreductases, and conjugating systems are of particular importance for increasing the polarity. The enzymes that modify the steroid nucleus are able to convert the nonpolar 3~hydroxyA5-steroid into a considerably more polar 5~holestane-?i~~,7~~-dihydroxyr 5pcholestane-Sa, 7a, 12a-trihydroxy steroid. The enzymes involved in these conversions are mainly located in the endoplasmic reticulum and the cytosol. The enzymes involved in the steroid side-chain degradation convert the highly nonpolar Cpsteroid side-chain into a chain-shortened carboxylic acid conjugated to an amino acid. These enzymes are mainly located in the mitochondria and in the peroxisomes. According to current concepts, the conversion of cholesterol into bile acids in mammals starts with the nuclear transformations, and most or all of these changes precede those of the steroid side-chain. Based on early in vivo and in vitro work on rats, the sequence of reactions shown in Fig. 1 was formulated about 25 years ago for the conversion of cholesterol into cholic and chenodeoxycholic acids. It is evident, however, that alternative pathways exist where some or most of the changes in the steroid side-chain precede the changes in the nucleus. As the flux of bile acids probably does not regulate any of the pathways where 7a-hydroxylation is not the first step, it seems that the cholesterol 7a-hydroxylase is the only enzyme that is capable of regulating the overall conversion into bile acids. The steroid side chain of plant sterols contains a methyl or an ethyl group in 24position. This means that the normal mechanism for side-chain degradation cannot be operative. In view of the very low degree of absorption of these steroids, there is less need for a specialized degradative enzyme. In at least one mammalian species, however, a system has been evolved that is able to convert plant sterols into highly polar conjugated Cnl-bile acids. In the present review, the emphasis is on the most important mechanism for steroid side-chain degradation in connection with bile acid biosynthesis, the 27-