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

研究成果: Article査読

40 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)201-208
ページ数8
ジャーナルBBA - General Subjects
1158
3
DOI
出版ステータスPublished - 1993 11 28
外部発表はい

ASJC Scopus subject areas

  • 生物理学
  • 生化学
  • 分子生物学

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