Metherall J E, Li H, Waugh K
Department of Human Genetics, University of Utah, Salt Lake City 84112, USA.
J Biol Chem. 1996 Feb 2;271(5):2634-40. doi: 10.1074/jbc.271.5.2634.
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.
多药耐药（MDR）P-糖蛋白最初因其在过度表达时能够催化肿瘤细胞中细胞毒性药物的ATP依赖性外排而被识别。尽管进行了广泛研究，但对于这些蛋白质的正常底物和正常细胞功能仍知之甚少。在随附的论文（Metherall, J. E., Waugh, K., and Li, H. (1996) J. Biol. Chem. 271, 2627 - 2633）中，我们证明孕酮抑制胆固醇生物合成，导致多种胆固醇前体的积累。在当前论文中，我们使用多种标准表明孕酮受体不参与这种抑制作用。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。我们表明甾体激素抑制胆固醇生物合成的能力与：1）其总体疏水性和2）其抑制MDR活性的能力相关。这一发现的唯一例外是β-雌二醇，它对胆固醇生物合成的抑制作用比仅基于疏水性和MDR抑制所预期的更强。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LDL衍生胆固醇的酯化需要MDR活性（P. DeBry和J. E. Metherall，已提交发表），我们研究了这些现象之间的关系，结果表明胆固醇酯化的抑制不会导致胆固醇生物合成的抑制，胆固醇生物合成的抑制也不会导致胆固醇酯化的抑制。我们提出了一个模型，其中MDR是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甾醇底物到达内质网驻留酶来防止胆固醇酯化和胆固醇生物合成。
