Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus

C. P.H. Yang, S. G. DePinho, L. M. Greenberger, R. J. Arceci, S. B. Horwitz

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)782-788
Number of pages7
JournalJournal of Biological Chemistry
Volume264
Issue number2
StatePublished - 1989

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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