Role of multidrug resistance P-glycoproteins in cholesterol biosynthesis
Role of multidrug resistance P-glycoproteins in cholesterol biosynthesis
复制标题
DOI：
10.1074/jbc.271.5.2634
复制
发表时间：
1996-02-02
影响因子：
4.8
通讯作者：
Waugh, K
中科院分区：
文献类型：
--
作者：
Metherall, JE;Li, HJ;Waugh, K
多药耐药（MDR）P-糖蛋白首先被认为是当其过表达时能够催化ATP依赖的细胞毒性药物从肿瘤细胞中流出。尽管进行了广泛的研究，但对这些蛋白质的正常底物和正常细胞功能知之甚少。Waugh，K.，和Li，H.（1996）J. Biol，Chem，271，2627-2633），我们证明孕酮抑制胆固醇生物合成，引起许多胆固醇前体的积累。在目前的手稿中，我们使用几个标准来表明孕酮受体不参与这种抑制，相反，我们证明孕酮通过干扰MDR活性来抑制胆固醇生物合成，我们表明类固醇激素抑制胆固醇生物合成的能力与以下因素相关：1）其一般疏水性和2）其抑制MDR活性的能力，该发现的唯一例外是β-雌二醇，其是比仅基于疏水性和MDR抑制的预期更有效的胆固醇生物合成抑制剂。我们进一步证明MDR的非甾体抑制剂也抑制胆固醇生物合成，由于MDR活性是LDL衍生的胆固醇的酯化所必需的（P. DeBry和J.E. Metherall，提交出版），我们研究了这些现象之间的关系，并表明胆固醇酯化的抑制不会引起胆固醇生物合成的抑制，并且胆固醇生物合成的抑制不会引起胆固醇酯化的抑制。我们提出了一个模型，其中MDR是将甾醇从质膜转运到内质网（ER）所必需的，抑制这种转运通过阻止固醇底物到达ER驻留酶来防止胆固醇酯化和胆固醇生物合成。
Multidrug resistance (MDR) P-glycoproteins were first recognized for their ability to catalyze ATP-dependent efflux of cytotoxic agents from tumor cells when overexpressed. Despite extensive study, little is known about the normal substrate(s) and normal cellular function of these proteins, In the accompanying manuscript (Metherall, J. E., Waugh, K., and Li, H. (1996) J. Biol, Chem, 271, 2627-2633), we demonstrate that progesterone inhibits cholesterol biosynthesis, causing the accumulation of a number of cholesterol precursors. In the current manuscript, we use several criteria to show that the progesterone receptor is not involved in this inhibition, Rather, we demonstrate that progesterone inhibits cholesterol biosynthesis by interfering with MDR activity, We show that a steroid hormone's ability to inhibit cholesterol biosynthesis is correlated with: 1) its general hydrophobicity and 2) its ability to inhibit MDR activity, The only exception to this finding is beta-estradiol, which is a more potent inhibitor of cholesterol biosynthesis than expected based solely on hydrophobicity and MDR inhibition, We further demonstrate that nonsteroidal inhibitors of MDR also inhibit cholesterol biosynthesis, Since MDR activity is required for esterification of LDL-derived cholesterol (P. DeBry and J. E. Metherall, submitted for publication), we investigated the relationship between these phenomena and show that inhibition of cholesterol esterification does not cause inhibition of cholesterol biosynthesis and that inhibition of cholesterol biosynthesis does not cause inhibition of cholesterol esterification, We propose a model in which MDR is required for transport of sterols from the plasma membrane to the endoplasmic reticulum (ER), Inhibiting this transport prevents cholesterol esterification and cholesterol biosynthesis by preventing sterol substrates from reaching ER-resident enzymes.