Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter

Bircsak, Kristin M.; Gupta, Vivek; Yuen, Poi Yu Sofia; Gorczyca, Ludwik; Weinberger, Barry; Vetrano, Anna M.; Aleksunes, Lauren M.

doi:10.1124/jpet.115.230185

Cited by 27 publications

(23 citation statements)

References 78 publications

(81 reference statements)

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“…RNA was isolated and qPCR performed as previously described [27]. Stem-loop reverse transcription real-time qPCR for microRNA (miRNA) was performed using the primers and methods as reported [20].…”

Section: Methodsmentioning

confidence: 99%

“…Proteins from cell homogenates (10µg) or placental microvillous membranes (15µg) were separated on SDS-polyacrylamide 4-12% Bis-Tris gels (Life Technologies) by electrophoresis [27]. The following antibodies were used: BCRP (BXP-53 Enzo LifeSciences, Farmingdale, NY, 1:5000), GLUT1 (Ab652 Abcam, Cambridge, MA, 1:1000) and β-ACTIN (Ab8227 Abcam, 1:2000).…”

Section: Methodsmentioning

confidence: 99%

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Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling

Francois

Gorczyca

et al. 2017

Placenta

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Introduction The BCRP/ABCG2 efflux transporter protects the developing fetus by limiting the transplacental transfer of drugs and chemicals and prevents the apoptosis of trophoblasts. The purpose of this study was to determine whether hypoxia-related signaling alters placental BCRP expression and function in vitro and in human pregnancies. Methods Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), or 3% oxygen for 24-48 h. Activation of HIF-1α signaling and regulation of BCRP was assessed using qPCR, ELISA, western blotting and a fluorescent substrate transport assay. In addition, healthy term placentas from high altitude pregnancies with chronic hypoxia were assessed for BCRP expression. Results CoCl2 and 3% oxygen increased HIF-1α protein signaling and decreased the mRNA and protein expression of BCRP by 30-75% in BeWo cells. Reduced BCRP expression corresponded with impaired efflux activity during hypoxia as evidenced by accumulation of the substrate Hoechst 33342. A number of transcription factors known to regulate BCRP, including AHR, NRF2 and PPARγ, were also coordinately down-regulated by 3% oxygen in BeWo cells. Moreover, women who gave birth at a high altitude (3100 m) exhibited signs of chronic placental hypoxia, including enhanced protein expression of the HIF-1α target GLUT1, and had reduced BCRP levels in microvillous membranes compared to women at a moderate altitude (1600 m). Discussion This study provides novel insight into the regulation of the placental BCRP transporter by hypoxia, which may be important for exposure of the fetus to chemicals during early development and in hypoxia-related pregnancy disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling

Francois

Gorczyca

et al. 2017

Placenta

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“…An interesting modulator of BCRP expression is hypoxia [86]. Drugs that are known substrates of BCRP include zidovudine, tenofovir disoproxil fumarate, bupropion, nitrofurantoin, and glyburide, to name a few [52,80,82,87,88]. Many of the substrates of BCRP are also substrates of P-gp, demonstrating redundancy in placental efflux capacity.…”

Section: Mechanisms Of Drug Transport Across the Placentamentioning

confidence: 99%

“…Many of the substrates of BCRP are also substrates of P-gp, demonstrating redundancy in placental efflux capacity. Efflux of glyburide by BCRP in the placenta is the likely cause of low fetal accumulation of glyburide, making it safe for use in gestational diabetes [87]. Genistein, an isoflavone and phytoestrogen, has been shown to both directly interfere with BCRP efflux and alter the transcription of BCRP, which may have clinical relevance for pregnant patients consuming soy products [87,89].…”

Section: Mechanisms Of Drug Transport Across the Placentamentioning

confidence: 99%

Placental control of drug delivery

Al-Enazy

Ali

Albekairi

et al. 2017

Advanced Drug Delivery Reviews

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The placenta serves as the interface between the maternal and fetal circulations and regulates the transfer of oxygen, nutrients, and waste products. When exogenous substances are present in the maternal bloodstream—whether from environmental contact, occupational exposure, medication, or drug abuse—the extent to which this exposure affects the fetus is determined by transport and biotransformation processes in the placental barrier. Advances in drug delivery strategies are expected to improve the treatment of maternal and fetal diseases encountered during pregnancy.

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“…BCRP transports substrates away from the placenta and prevents the accumulation of potentially harmful xenobiotics in the fetus [3]. Substrates include commonly prescribed drugs such as the hypoglycemic agent glyburide, the chemotherapeutic drug doxorubicin and the antibiotic nitrofurantoin [4–7]. BCRP also transports estrogenic dietary chemicals that affect sexual differentiation of the fetus including the fungal toxin zearalenone [8–11].…”

Section: Introductionmentioning

confidence: 99%

Localization of the placental BCRP/ ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity

et al. 2017

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Introduction The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro. Methods BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl-β-cyclodextrin (MβCD, 5mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200μM, 48 h). Results and Discussion BCRP was found to co-localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MβCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MβCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts.

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Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter

Cited by 27 publications

References 78 publications

Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling

Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling

Placental control of drug delivery

Localization of the placental BCRP/ ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity

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