Progesterone and its metabolites: the potent inhibitors of the transporting activity of P-glycoprotein in the adrenal gland

Misako Ichikawa-Haraguchi, Tomoyuki Sumizawa, Akihiko Yoshimura, Tatsuhiko Furukawa, Shigeru Hiramoto, Masanori Sugita, Shin ichi Akiyama

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37 Citations (Scopus)

Abstract

P-glycroprotein (P-gp) is a transmembrane glycoprotein responsible for the multidrug resistant (MDR) phenotype in various cancer cells. It has been shown that P-gp transports various kinds of anti-cancer agents as well as hydrophobic chemicals. Although P-gp is also expressed in normal human tissues, such as liver, kidney, and adrenal gland, its function and transporting substrates in these tissues are still unknown. In previous work, we demonstrated that some compounds in human plasma modulate the transporting activity of P-gp. We also found that P-gp is expressed at a high level in the bovine adrenal gland and that this tissue contains large amount of compounds which inhibit the transporting activity of P-gp. We purified such compounds from the adrenal gland by monitoring the ability to enhance the accumulation of [3H]vincristine in MDR cells. Two majo compounds were purified and identified as progesterone and pregnenolone by nuclear magnetic resonance (NMR) analysis. Progesterone was the most potent and abundant compound that inhibited the transporting activity of P-gp among the compounds extracted from bovine adrenal gland with methanol. We also found that six authentic progesterone metabolites in the 5β-metabolic pathway but none in 5α-metabolic pathway were able to enhance the accumulation of [3H]vincristine in MDR cells and to inhibit [3H]azidopien photolabeling of P-gp in the adrenal gland. These results indicate that some progesterone metabolites can interact with P-gp and that stereoisomerism around carbon 5 of the progesterone metabolites is important for them to recognized by P-gp.

Original languageEnglish
Pages (from-to)201-208
Number of pages8
JournalBBA - General Subjects
Volume1158
Issue number3
DOIs
Publication statusPublished - 1993 Nov 28

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Keywords

  • (Adrenal gland)
  • Glycoprotein
  • Multidrug resistance
  • P-glycorprotein
  • Progesterone
  • Progesterone metabolite
  • Transport activity

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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