Wang Honggang, Zhou Lin, Gupta Anshul, Vethanayagam R Robert, Zhang Yi, Unadkat Jashvant D, Mao Qingcheng
Dept. of Pharmaceutics, School of Pharmacy, Univ. of Washington, Seattle, WA 98195-7610, USA.
Am J Physiol Endocrinol Metab. 2006 May;290(5):E798-807. doi: 10.1152/ajpendo.00397.2005. Epub 2005 Dec 13.
The breast cancer resistance protein (BCRP) is abundant in the placenta and protects the fetus by limiting placental drug penetration. We hypothesize that pregnancy-specific hormones regulate BCRP expression. Hence, we examined the effects of progesterone (P4) and 17beta-estradiol (E2) on BCRP expression in the human placental BeWo cells. P4 and E2 significantly increased and decreased BCRP protein and mRNA, respectively. Likewise, treatment with P4 and E2 increased and decreased, respectively, fumitremorgin C-inhibitable mitoxantrone efflux activity of BeWo cells. Reduction in BCRP expression by E2 was abrogated by the estrogen receptor (ER) antagonist ICI-182,780. However, the progesterone receptor (PR) antagonist RU-486 had no effect on P4-mediated induction of BCRP. P4 together with E2 further increased BCRP protein and mRNA compared with P4 treatment alone. This combined effect on BCRP expression was abolished by RU-486, ICI-182,780, or both. Further analysis revealed that E2 significantly decreased ER beta mRNA and strongly induced PR(B) mRNA in a dose-dependent manner but had no effect on PR(A) and ER alpha. P4 alone had no significant effect on mRNA of ER alpha, ER beta, PR(A), and PR(B). E2 in combination with P4 increased PR(B) mRNA, but the level of induction was significantly reduced compared with E2 treatment alone. Taken together, these results indicate that E2 by itself likely downregulates BCRP expression through an ER, possibly ER beta. P4 alone upregulates BCRP expression via a mechanism other than PR. P4 in combination with E2 further increases BCRP expression, presumably via a nonclassical PR- and/or E2-mediated synthesis of PR(B).
乳腺癌耐药蛋白（BCRP）在胎盘中含量丰富，通过限制胎盘药物渗透来保护胎儿。我们推测妊娠特异性激素调节BCRP表达。因此，我们研究了孕酮（P4）和17β-雌二醇（E2）对人胎盘BeWo细胞中BCRP表达的影响。P4和E2分别显著增加和降低了BCRP蛋白和mRNA水平。同样，用P4和E2处理分别增加和降低了BeWo细胞中夫马洁林C抑制的米托蒽醌外排活性。雌激素受体（ER）拮抗剂ICI-182,780消除了E2对BCRP表达的降低作用。然而，孕酮受体（PR）拮抗剂RU-486对P4介导的BCRP诱导没有影响。与单独用P4处理相比，P4与E2共同作用进一步增加了BCRP蛋白和mRNA水平。RU-486、ICI-182,780或两者共同作用消除了对BCRP表达的这种联合效应。进一步分析表明，E2以剂量依赖方式显著降低ERβ mRNA并强烈诱导PR(B) mRNA，但对PR(A)和ERα没有影响。单独使用P4对ERα、ERβ、PR(A)和PR(B)的mRNA没有显著影响。E2与P4联合增加了PR(B) mRNA，但诱导水平与单独用E2处理相比显著降低。综上所述，这些结果表明E2本身可能通过ER，可能是ERβ下调BCRP表达。单独使用P4通过PR以外的机制上调BCRP表达。P4与E2联合进一步增加BCRP表达，推测是通过非经典PR和/或E2介导的PR(B)合成。
