The role of cytochrome P450 in the regulation of cholesterol biosynthesis
The role of cytochrome P450 in the regulation of cholesterol biosynthesis
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DOI：
10.1007/s11745-002-1016-x
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发表时间：
2002-12-01
期刊：
影响因子：
1.9
通讯作者：
Gibbons, GF
中科院分区：
文献类型：
--
作者：
Gibbons, GF
细胞色素P450超家族的一个普遍表达的成员CYP 51编码羊毛甾醇14 α-脱甲基酶，这是哺乳动物中羊毛甾醇转化为胆固醇的第一步。羊毛甾醇14 α-去甲基化的生物合成中间体是氧化甾醇，其在体外抑制哺乳动物细胞中的HMG-CoA还原酶和甾醇合成。这些氧固醇（5 α-羊毛脂-8-烯-30，32-二醇和3 β-羟基-5 α-羊毛脂-8-烯-32-醛）在体外有效地转化为胆固醇，并且通常被认为是天然胆固醇前体。当以高浓度加入肝细胞时，除了转化为胆固醇外，它们还迅速代谢为极性更强的甾醇和甾醇酯。5 α-羊毛甾-8-烯-3 β-醇的15 α-和15 β-羟基差向异构体也可快速代谢为极性更强的甾醇和甾醇酯，但不能有效转化为胆固醇。所有这些氧化固醇的极性固醇形成依赖于细胞色素P450的活性形式。氧固醇是固醇调节元件结合蛋白家族和肝X-受体α的转录因子活性的有效调节剂。有人提出，快速，细胞色素P450依赖性代谢的天然存在的监管氧化固醇提供了一种途径，使他们成为无法影响基因转录的失活。药物酮康唑对细胞色素P450的抑制可防止此类氧化固醇的失活，导致体内和体外肝HMG-CoA还原酶的长期抑制。
A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51, encodes lanosterol 14alpha-demethylase, the first step in the conversion of lanosterol into cholesterol in mammals. The biosynthetic intermediates of lanosterol 14alpha-demethylation are oxysterols, which inhibit HMG-CoA reductase and sterol synthesis in mammalian cells in vitro. These oxysterols (5alpha-lanost-8-en-3beta,32-diol and 3beta-hydroxy-5alpha-lanost-8-en-32-al) are efficiently converted into cholesterol in vitro and are generally considered to be natural cholesterol precursors. When added to hepatocytes in high concentrations, besides their conversion into cholesterol, they are also rapidly metabolized into more polar sterols and into steryl esters. The 15alpha- and 15beta-hydroxy epimers of 5alpha-lanost-8-en-3beta-ol are also rapidly metabolized into more polar sterols and steryl esters but are not converted efficiently into cholesterol. Polar sterol formation from all these oxysterols is dependent on an active form of cytochrome P450. Oxysterols are potent regulators of the activities of transcription factors of the sterol regulatory element-binding protein family and of liver X-receptor alpha. It is proposed that the rapid, cytochrome P450-dependent metabolism of naturally occurring regulatory oxysterols provides a route for their deactivation so that they become incapable of affecting gene transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents the inactivation of such oxysterols, leading to a prolonged suppression of hepatic HMG-CoA reductase in vivo and in vitro.