Barnes K M, Dickstein B, Cutler G B, Fojo T, Bates S E
Developmental Endocrinology Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
Biochemistry. 1996 Apr 16;35(15):4820-7. doi: 10.1021/bi952380k.
According to multiple reports, progesterone is not transported by P-glycoprotein (Pgp), which mediates multidrug resistance through active drug efflux. However, progesterone has been shown to block Pgp- mediated efflux of other drugs. To extend these observations and to examine the effect of modulating Pgp phosphorylation, the accumulation of progesterone and 14 other steroids in untreated and calphostin C-treated multidrug-resistant human colon carcinoma SW620 Ad300 cells was compared to the accumulation in parental SW620 cells. However, the accumlation of more hydrophilic steroids was reduced by as much as 50%. Progesterone and progesterone-like compounds, however were potent inhibitors of Pgp-mediated vinblastine efflux; increased antagonism correlated with increased steroid hydrophobicity. Treatment with calphostin C, a PKC inhibitor which decreases Pgp phosphorylation, increased progesterone efflux, modulated Pgp antagonism by steroids, and inhibited photoaffinity labeling of Pgp by progesterone. These results extend previous observations that Pgp can mediate the transport of, and be antagonized by, a variety of steroids and that these properties vary with both steroid's hydrophobicity and the phosphorylated state of Pgp.
根据多项报道，孕酮不是由P-糖蛋白（Pgp）转运的，P-糖蛋白通过主动药物外排介导多药耐药性。然而，已证明孕酮可阻断Pgp介导的其他药物外排。为了扩展这些观察结果并研究调节Pgp磷酸化的作用，将孕酮和其他14种甾体在未处理和经钙磷蛋白C处理的多药耐药人结肠癌SW620 Ad300细胞中的蓄积情况与亲代SW620细胞中的蓄积情况进行了比较。然而，亲水性更强的甾体的蓄积减少了多达50%。然而，孕酮和孕酮样化合物是Pgp介导的长春碱外排的有效抑制剂；拮抗作用增强与甾体疏水性增加相关。用钙磷蛋白C（一种可降低Pgp磷酸化的蛋白激酶C抑制剂）处理，可增加孕酮外排，调节甾体对Pgp的拮抗作用，并抑制孕酮对Pgp的光亲和标记。这些结果扩展了先前的观察结果，即Pgp可介导多种甾体的转运并被其拮抗，且这些特性随甾体的疏水性和Pgp的磷酸化状态而变化。
