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

Evseenko, Denis; Paxton, James W.; Keelan, Jeffrey A.

doi:10.1124/dmd.106.011478

Cited by 166 publications

(159 citation statements)

References 42 publications

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“…Interestingly, a down-regulation in Bcrp expression was detected in both the placental trophoblast cells and fetal capillary endothelium of endotoxin-treated animals. A decrease in the in vitro expression of Bcrp in primary term trophoblasts was recently reported after exposure to TNF-␣ or IL-1␤ (Evseenko et al, 2007). Consistent with these in vitro findings, our results demonstrate a significant induction of TNF-␣ and IL-6 in the maternal plasma of endotoxin-treated rats.…”

Section: Effect Of Endotoxin On Placental Drug Transporterssupporting

confidence: 81%

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Petrović

Wang²,

Piquette-Miller

2008

Drug Metab Dispos

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ABSTRACT:On average, 80% of pregnant women consume over-the-counter and/or prescription medications. The placenta is a crucial organ that can restrict fetal drug exposure. ATP-binding cassette (ABC) drug transporters play an important role in the placenta because they limit the transplacental transfer of xenobiotics. However, the impact of infection or inflammation on placental drug transporters is not well established. Thus, we examined the impact of endotoxin-induced inflammation on the placental expression of several key drug transporters in rats and its impact on fetal exposure to a drug substrate. Real-time polymerase chain reaction results demonstrated a significant time-and dose-dependent down-regulation of breast cancer resistance protein/Abcg2 mRNA in the placentas of endotoxin-treated rats with a corresponding decrease in protein levels. Likewise, the mRNA levels of several other ABC transporters (Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3) and members of the organic anion-transporting polypeptides (Slco1a4, Slco2b1, Slco4a1) were down-regulated. A biodistribution study was carried out with glyburide, a hypoglycemic sulfonylurea substrate of both ABC efflux and Oatp uptake transporters. Although administration of endotoxin resulted in comparable plasma concentrations of glyburide, a pronounced increase in the accumulation of glyburide was seen in the fetuses of endotoxin-treated rats (162% of controls, p < 0.01). Glyburide plasma protein binding was not affected by endotoxin treatment. Overall, our results demonstrated a significant reduction in the placental expression of several important drug transporters during endotoxin-induced inflammation. Alterations in glyburide distribution highlight the potential importance of both influx and efflux placental transporters in impacting fetal drug exposure.

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Section: Effect Of Endotoxin On Placental Drug Transporterssupporting

confidence: 81%

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Petrović

Wang²,

Piquette-Miller

2008

Drug Metab Dispos

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“…Our findings differ from prior literature reports noting transporter down-regulation during inflammation caused by inflammatory cytokines such as TNF-␣, IL-6, and endotoxin (i.e., LPS) in rats (Sukhai et al, 2001;Chen et al, 2005;Wang et al, 2005) and human primary placental cells (Evseenko et al, 2007). We offer several possible explanations for these differences: the impact of LPS-induced inflammation on drug transporters has yet to be evaluated at different gestational stages, and previous reports have indicated that preterm placentas respond differently to LPS than those at term, specifically in their patterns of cytokine release (Holcberg et al, 2007).…”

Section: Mason Et Alcontrasting

confidence: 56%

ATP-Binding Cassette Transporter Expression in Human Placenta as a Function of Pregnancy Condition

Mason

Buhimschi²,

Buhimschi³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Fetal drug exposure is determined by the type and concentration of placental transporters, and their regulation is central to the development of new treatments and delivery strategies for pregnant women and their fetuses. We tested the expression of several clinically important transporters in the human placenta associated with various pregnancy conditions (i.e., labor, preeclampsia, and preterm labor-inflammation). Placentas were obtained from five groups of women at the time of primary cesarean section: 1) term no labor; 2) term labor; 3) preterm no labor (delivered for severe preeclampsia); 4) preterm labor without inflammation (PTLNI); and 5) preterm labor with inflammation (PTLI). Samples were analyzed by Western blot and immunohistochemistry to identify changes in protein expression. Relative mRNA expression was determined by quantitative real-time polymerase chain reaction. A functional genomic approach was used to identify placental gene expression and elucidate molecular events that underlie the given condition. Placental expression of ATP-binding cassette transporters from women in labor and women with preeclampsia was unaltered. Multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) and mRNA expression increased in placentas of women with preterm labor with inflammation. Molecular pathways of genes up-regulated in PTLI samples included cytokinecytokine receptor interactions and inflammatory response compared with those in the PTLNI group. The mRNA expression of MDR1 and BCRP was correlated with that of interleukin-8, which also increased significantly in PTLI samples. These data suggest that the transfer of drugs across the placenta may be altered in preterm pregnancy conditions associated with inflammation through changes in MDR1 and BCRP.

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“…Cells were collected as mononuclear CTB at 2 h and grown for a further 72 h in M199 media supplemented with 10% FCS, 100 U/ml penicillin and 100 mg/ml streptomycin in 5% CO 2 humidified atmosphere at 37 8C. CTB purity was confirmed by the proportion of CK7-positive trophoblast cells in the culture, which was 95G 3.14% (nZ3) (Evseenko et al 2007a).…”

Section: Third-trimester Placental Ctbsmentioning

confidence: 99%

“…Placentae (nZ10) were obtained with informed consent from women after delivery by Caesarean section at term, and CTBs were isolated using trypsin digestion as described previously (Evseenko et al 2007a). Briefly, villous tissue from term placentae were subjected to eight consecutive digestions in 0.25% trypsin and cells were isolated by centrifugation at 300 g for 7 min.…”

Section: Third-trimester Placental Ctbsmentioning

confidence: 99%

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Borg¹,

Yong²,

Lappas³

et al. 2015

Reproduction

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Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK-STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK-STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK-STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2, differentiation marker CGB/human chorionic gonadotrophin betasubunit (b-hCG) and apoptosis markers caspases 3 and 8, and TP53. Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3, STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3, the mRNA and protein levels of CGB/b-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies.

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

Cited by 166 publications

References 42 publications

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

ATP-Binding Cassette Transporter Expression in Human Placenta as a Function of Pregnancy Condition

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

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