Yang C P, DePinho S G, Greenberger L M, Arceci R J, Horwitz S B
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
J Biol Chem. 1989 Jan 15;264(2):782-8.
P-Glycoprotein (P-GP) plays a pivotal role in maintaining the multidrug-resistant (MDR) phenotype. This membrane glycoprotein is overproduced in MDR cells and the endometrium of the mouse gravid uterus (Arceci, R.J., Croop, J.M., Horwitz, S.B., and Housman, D. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 4350-4354). This latter observation and an interest in endogenous substrates for P-GP led to a study of the interaction of steroids with P-GP found in the endometrium of the mouse gravid uterus and in MDR cells derived from the murine macrophage-like cell J774.2. [3H]Azidopine labeling of P-GP from these two sources was inhibited by various steroids, particularly progesterone. Progesterone also markedly inhibited [3H]vinblastine binding to membrane vesicles prepared from MDR cells, enhanced vinblastine accumulation in MDR cells, and increased the sensitivity of MDR cells to vinblastine. In addition, we have demonstrated that the hydrophobicity of a steroid is important in determining its effect on inhibition of drug binding to P-GP. It is concluded that progesterone, a relatively nontoxic endogenous steroid, interacts with P-GP and is capable of reversing drug resistance in MDR cells.
P-糖蛋白（P-GP）在维持多药耐药（MDR）表型中起关键作用。这种膜糖蛋白在MDR细胞和小鼠妊娠子宫的子宫内膜中过量产生（Arceci, R.J., Croop, J.M., Horwitz, S.B., and Housman, D. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 4350 - 4354）。后一观察结果以及对P-GP内源性底物的兴趣，促使人们对类固醇与在小鼠妊娠子宫子宫内膜和源自鼠巨噬细胞样细胞J774.2的MDR细胞中发现的P-GP之间的相互作用进行研究。来自这两种来源的P-GP的[3H]叠氮平标记受到各种类固醇的抑制，尤其是孕酮。孕酮还显著抑制[3H]长春碱与从MDR细胞制备的膜囊泡的结合，增强长春碱在MDR细胞中的积累，并增加MDR细胞对长春碱的敏感性。此外，我们已经证明类固醇的疏水性在决定其对抑制药物与P-GP结合的作用方面很重要。得出的结论是，孕酮是一种相对无毒的内源性类固醇，它与P-GP相互作用并能够逆转MDR细胞中的耐药性。
