17β-Estradiol and Progesterone Concentrations in Myometrium of Pregnancy and Their Relationships to Concentrations in Peripheral Plasma*

Batra, Satish; Bengtsson, Lars Philip

doi:10.1210/jcem-46-4-622

Cited by 36 publications

(18 citation statements)

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“…M during pregnancy (2,11). However, we did not observe any significant effect of E 2 on hOAT4 activity within a concentration range of 10 Ϫ8 -10 Ϫ5 M (Fig.…”

Section: ϫ7mentioning

confidence: 54%

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

Zhou¹,

You²

2007

American Journal of Physiology-Endocrinology and Metabolism

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Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17␤-estradiol (E2) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time-and concentration-dependent downregulation of hOAT4 transport activity, whereas E2 had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased Vmax without significant change in Km. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, P4 regulates hOAT4 activity by mechanisms independent of PKC pathway. acute regulation HUMAN ORGANIC ANION TRANSPORTER 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories (3,7,18,19,24). hOAT4 is abundantly expressed in the kidney and placenta (4). In the kidney, OAT4 functions as an organic anion/dicarboxylate exchanger at the apical membrane of the proximal tubule and is responsible for the reabsorption of organic anions driven by an outwardly directed dicarboxylate gradient (6). In the placenta, hOAT4 is localized to the basolateral membrane of syncytiotrophoblasts (20). It is believed that estrogen biosynthesis in the placenta uses dehydroepiandrosterone sulfate (DHEAS), a precursor produced in large amount by the fetal adrenals. Accumulation of excess DHEAS is associated with intrauterine growth retardation (17). DHEAS is an OAT4 substrate. Therefore, OAT4 may play an important role in efficient uptake of DHEAS by the placenta for the production of estrogens and for the protection of fetus from the cytotoxicity of DHEAS.Computer modeling has shown that hOAT4 contains multiple potential glycosylation sites in its first extracellular loop. The glycosylation process occurs in two major steps: the first step is the addition of oligosaccharides to the nascent protein, and the second step is the processing of added oligosaccharides during which the added oligosaccharides are modified and trimmed. Our group (27) previously sho...

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“…M during pregnancy (2,11). However, we did not observe any significant effect of E 2 on hOAT4 activity within a concentration range of 10 Ϫ8 -10 Ϫ5 M (Fig.…”

Section: ϫ7mentioning

confidence: 54%

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

Zhou¹,

You²

2007

American Journal of Physiology-Endocrinology and Metabolism

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“…The plasma E 2 concentration during pregnancy increases steadily to around 0.8 ϫ 10 Ϫ7 M at term (3,20). At concentrations observed during pregnancy (10 Ϫ8 and 10 Ϫ7 M), E 2 significantly decreased BCRP protein (Fig.…”

Section: Discussionmentioning

confidence: 81%

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

Wang

Zhou

Gupta

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

145

122

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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␤-estradiol (E2) on BCRP expression in the human placental BeWo cells. P 4 and E2 significantly increased and decreased BCRP protein and mRNA, respectively. Likewise, treatment with P 4 and E2 increased and decreased, respectively, fumitremorgin C-inhibitable mitoxantrone efflux activity of BeWo cells. Reduction in BCRP expression by E 2 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. P4 together with E2 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␤ mRNA and strongly induced PRB mRNA in a dose-dependent manner but had no effect on PR A and ER␣. P4 alone had no significant effect on mRNA of ER␣, ER␤, PRA, and PR B. E2 in combination with P4 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␤. P 4 alone upregulates BCRP expression via a mechanism other than PR. P 4 in combination with E2 further increases BCRP expression, presumably via a nonclassical PR-and/or E 2-mediated synthesis of PRB. hormonal regulation; ATP-binding cassette transporter; pregnancy THE BREAST CANCER RESISTANCE PROTEIN (BCRP) is the second member (gene symbol ABCG2) of the subfamily G of the large ATP-binding cassette (ABC) transporter superfamily (1, 9, 25). BCRP is highly expressed in many normal tissues, including the epithelium of the small intestine and the liver canalicular membrane (22). Therefore, in addition to conferring resistance in cancer cells to chemotherapeutic agents such as mitoxantrone (MX), topotecan, and methotrexate (8,9,25,36), BCRP has been shown to mediate apically-directed drug transport and play a significant role in absorption, distribution, and elimination of BCRP substrates (4,19,21,32,35). Of interest is that BCRP is also abundantly expressed in the apical membrane of placental syncytiotrophoblasts (22). Whereas the precise physiological role of BCRP in the placenta is still unclear, existing data suggest that BCRP may protect the fetus against toxic substances/drugs and metabolites by extruding them across the placental barrier. For example, Bcrp1, the murine homolog of BCRP, has been shown to significantly alter fetal distribution of topotecan, a BCRP substrate. The fetus/plasma ratio of topotecan was increased twofold in pregnant mice treated with the BCRP inhibitor GF-120918 compared with the vehicle-treatment control (19).Distribution of drugs that are BCRP substrate...

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“…In the same study, P 4 was observed to be a BCRP inducer, but this effect was detectible only at very high concentrations (Ͼ1 M) (Wang et al, 2006). Circulating estradiol and P 4 concentrations in late pregnancy reach approximately 50 and 500 nM at term, respectively (Batra and Bengtsson 1978;Khan-Dawood and Dawood 1984). Although the free fraction is likely to be much less than this (5-50%, depending on the steroid and gestational age), secretion of these steroids by the placenta is likely to result in increased local concentrations.…”

Section: Regulation Of Placental Abc Transportersmentioning

confidence: 81%

“…Test substances were added as follows: TNF-␣ (20 ng/ml), IL-1␤ (2 ng/ml), IL-6 (20 ng/ml), EGF (10 ng/ml), IGF-II (25 ng/ml), estradiol (100 nM), and P 4 (100 nM). With the exception of TNF-␣, these concentrations were selected to achieve levels that approximate maximal physiological concentrations reported in either peripheral or extracellular fluids (Batra and Bengtsson, 1978;Khan-Dawood and Dawood, 1984;Barreca et al, 1998;Kim et al, 2000;Inada et al, 2001;Lee and Piquette-Miller, 2003). With respect to TNF-␣, because of its potential to induce trophoblast apoptotic death, 20 ng/ml was selected for these studies, representing the maximal concentration that could be used without exerting significant (Ͼ10%) loss of viability (as assessed by MTT assay) over 48 h of treatment.…”

Section: Methodsmentioning

confidence: 99%

Independent Regulation of Apical and Basolateral Drug Transporter Expression and Function in Placental Trophoblasts by Cytokines, Steroids, and Growth Factors

Evseenko

Paxton²,

Keelan³

2007

Drug Metabolism and Disposition

166

135

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ABSTRACT:Placental ATP binding cassette (ABC) transporters protect placental and fetal tissues by effluxing xenobiotics and endogenous metabolites. We have investigated the effects of cytokines and survival/growth factors, implicated in various placental pathologies, on ABC transporter expression and function in primary placental trophoblast cells. Treatment of primary term trophoblasts in vitro with tumor necrosis factor-␣ (TNF-␣) or interleukin (IL)-1␤ decreased mRNA and protein expression of apical transporters ABCB1/multidrug resistance gene product 1 (MDR1) and ABCG2/ breast cancer resistance protein (BCRP) protein by 40 to 50% (P < 0.05). In contrast, IL-6 increased mRNA and protein expression of the basolateral transporter ABCB4/MDR3 (P < 0.05), whereas ABCC1/MRP1 expression was unaltered. Pretreatment of trophoblasts with TNF-␣ over 48 h resulted in significantly decreased BCRP efflux activity (increased mitoxantrone accumulation) with minimal changes in MDR1/3 activity. Epidermal growth factor (EGF) and insulin-like growth factor II, on the other hand, significantly increased BCRP expression at the mRNA and protein level (P < 0.05); EGF treatment also increased BCRP functional activity. Estradiol stimulated BCRP, MDR1, and MDR3 mRNA and protein expression by 40 to 60% and increased MDR1/3 functional activity (P < 0.05). Progesterone had modest positive effects on MRP1 mRNA and MDR1 protein expression (P < 0.05). In conclusion, this study shows that proinflammatory cytokines, sex steroids, and growth factors exert independent effects on expression of apical and basolateral placental ABC transporters in primary trophoblast. Such changes could alter placental drug disposition, increase fetal susceptibility to toxic xenobiotics, and impact on placental viability and function.

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17β-Estradiol and Progesterone Concentrations in Myometrium of Pregnancy and Their Relationships to Concentrations in Peripheral Plasma*

Cited by 36 publications

References 0 publications

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

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

Independent Regulation of Apical and Basolateral Drug Transporter Expression and Function in Placental Trophoblasts by Cytokines, Steroids, and Growth Factors

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