Regulation of BCRP/ABCG2 expression by progesterone and 17β-estradiol in human placental BeWo cells

被引:129
作者
Wang, HG [1 ]
Zhou, L [1 ]
Gupta, A [1 ]
Vethanayagam, RR [1 ]
Zhang, Y [1 ]
Unadkat, JD [1 ]
Mao, QC [1 ]
机构
[1] Univ Washington, Dept Pharmaceut, Sch Pharm, Seattle, WA 98195 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2006年 / 290卷 / 05期
关键词
hormonal regulation; ATP; binding cassette transporter; pregnancy;
D O I
10.1152/ajpendo.00397.2005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (P-4) and 17 beta-estradiol (E-2) on BCRP expression in the human placental BeWo cells. P-4 and E-2 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 P-4-mediated induction of BCRP. P-4 together with E-2 further increased BCRP protein and mRNA compared with P-4 treatment alone. This combined effect on BCRP expression was abolished by RU-486, ICI-182,780, or both. Further analysis revealed that E-2 significantly decreased ER beta mRNA and strongly induced PRB mRNA in a dose-dependent manner but had no effect on PRA and ER alpha. P-4 alone had no significant effect on mRNA of ER, ER beta, PRA, and PRB. E-2 in combination with P-4 increased PRB mRNA, but the level of induction was significantly reduced compared with E-2 treatment alone. Taken together, these results indicate that E-2 by itself likely downregulates BCRP expression through an ER, possibly ER alpha. P-4 alone upregulates BCRP expression via a mechanism other than PR. P-4 in combination with E-2 further increases BCRP expression, presumably via a nonclassical PR- and/or E-2-mediated synthesis of PRB.
引用
收藏
页码:E798 / E807
页数:10
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