P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells

被引:56
作者
Mark, Peter J. [1 ]
Waddell, Brendan J. [1 ]
机构
[1] Univ Western Australia, Sch Anat & Human Biol, Crawley, WA 6009, Australia
关键词
D O I
10.1210/en.2006-0633
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Exposure of the fetus and placenta to maternal glucocorticoids is normally limited by the placental glucocorticoid barrier, which consists primarily of placental 11 beta-hydroxysteroid dehydrogenase type 2-mediated conversion of cortisol to the biologically inactive cortisone. Studies in the rodent brain show that P-glycoprotein (P-gp) is also an important physiological regulator of glucocorticoid access to the glucocorticoid receptor (GR) in target cells because it exports cortisol back into peripheral circulation against a concentration gradient. Whether P-gp of placental origin also has this capacity is unknown. Therefore, we used the human placental choriocarcinoma cell line BeWo and its daughter cell line, BeWoMDR, virally transduced with P-gp, to assess whether placental P-gp regulates access of glucocorticoids to the GR. Quantitative PCR showed that BeWoMDR cells express approximately 10-fold higher levels of P-gp mRNA than BeWo cells, and syncytialization increased P-gp mRNA by approximately 7-fold. Elevated P-gp expression in BeWoMDR cells reduced activation of the GR by dexamethasone and cortisol (10(-9) to 10(-6)M) to around 40% of that in BeWo cells. Inhibition of P-gp-mediated glucocorticoid efflux by cyclosporin A in BeWoMDR cells returned GR activation to levels similar to those in BeWo cells. Diffusion of dexamethasone across BeWoMDR monolayers occurred at a slower rate than that across BeWo monolayers, but this difference was eliminated by cyclosporin A. These data support the hypothesis that P-gp contributes to the placental glucocorticoid barrier. Thus, 11 beta-hydroxysteroid dehydrogenase type 2 and P-gp may act in unison to reduce fetal and placental exposure to maternal and thereby minimize their growth inhibitory actions.
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页码:5147 / 5152
页数:6
相关论文
共 48 条
[1]  
[Anonymous], 1983, Statistical methods
[2]   Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer [J].
Atkinson, DE ;
Greenwood, SL ;
Sibley, CP ;
Glazier, JD ;
Fairbairn, LJ .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2003, 285 (03) :C584-C591
[3]   REGULATION OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY IN THE BABOON PLACENTA BY ESTROGEN [J].
BAGGIA, S ;
ALBRECHT, ED ;
PEPE, GJ .
ENDOCRINOLOGY, 1990, 126 (05) :2742-2748
[4]   Dual function of 11β-hydroxysteroid dehydrogenase in placenta:: Modulating placental glucocorticoid passage and local steroid action [J].
Burton, PJ ;
Waddell, BJ .
BIOLOGY OF REPRODUCTION, 1999, 60 (02) :234-240
[5]   INVITRO DETERMINATION OF RELATIVE CORTICOSTEROID POTENCY [J].
CANTRILL, HL ;
WALTMAN, SR ;
PALMBERG, PF ;
ZINK, HA ;
BECKER, B .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1975, 40 (06) :1073-1077
[6]  
COLE SPC, 1994, CANCER RES, V54, P5902
[7]   The insulin-like growth factors and feto-placental growth [J].
Fowden, AL .
PLACENTA, 2003, 24 (8-9) :803-812
[8]   Placental insufficiency and its consequences [J].
Gagnon, R .
EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY, 2003, 110 :S99-S107
[9]   Peptidylprolyl cis/trans isomerases (immunophilins): Biological diversity targets - Functions [J].
Galat, A .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2003, 3 (12) :1315-1347
[10]   FUNCTIONAL DOMAINS OF THE HUMAN GLUCOCORTICOID RECEPTOR [J].
GIGUERE, V ;
HOLLENBERG, SM ;
ROSENFELD, MG ;
EVANS, RM .
CELL, 1986, 46 (05) :645-652