Equilibrative Nucleoside Transporter 1 (ENT1, <i>SLC29A1</i>) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta

Červený, Lukáš; Ptackova, Zuzana; Čečková, Martina; Karahoda, Rona; Karbanova, Sara; Jirásková, Lucie; Greenwood, Susan; Glazier, Jocelyn D.; Štaud, František

doi:10.1124/dmd.118.083329

Cited by 27 publications

(28 citation statements)

References 60 publications

(117 reference statements)

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“…ENTs are widely expressed in various tissues, and ENTs contribute to the transport of endogenous nucleosides and various anticancer and antiviral nucleoside drugs, such as adenosine, gemcitabine, ribavirin, and abacavir (27)(28)(29)(30). Our data revealed that NBTI and dipyridamole (two ENT-specific inhibitors) strongly inhibited FTC uptake in BeWo cells and PHTCs and that NBTI inhibited FTC accumulation in JEG-3 cells (see Fig.…”

Section: Discussionsupporting

confidence: 50%

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Zeng

Bai

et al. 2019

Antimicrob Agents Chemother

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Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.

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Section: Discussionsupporting

confidence: 50%

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Zeng

Bai

et al. 2019

Antimicrob Agents Chemother

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“…13 ENT1 protein was found to be the predominant nucleoside transporter in placental MVMs (Table 1), as has already been confirmed at the functional and expressional levels. [8][9][10][11][12][13] The expression of ENT2 protein at human placental MVMs was under the limit of quantification according to our quantification analysis criteria, but this does not directly mean the absence of ENT2 protein. In fact, a positive peak was detected for 3 of 4 donors when only the most sensitive SRM transition for human ENT2 was considered, with a mean value of 0.74 fmol/mg protein (Supplemental Table S2).…”

Section: Discussionmentioning

confidence: 91%

“…11 In the rat placental barrier, the functional expression of ENT2 in placental MVM vesicles was suggested by the observation that adenosine uptake is more potently inhibited by NBMPR at 100 mM than at 0.1 mM, 10 which is inconsistent with the observation in human placental MVMs. 12 The involvement of CNTs in the uptake of the nucleoside was undetected neither in rat placental MVM vesicles. 10 Absolute quantification of nucleoside transporter proteins in placental MVMs using liquid chromatography-tandem mass spectrometry (LC-MS/ MS) should enable us to resolve these discrepancies and estimate the transport capacities of individual transporters at the placental MVMs based on the absolute protein expression levels.…”

Section: Introductionmentioning

confidence: 96%

“…6,7 Among these transporters, ENT1, encoded by SLC29A1, is expressed at the microvillous membrane (MVM) of the syncytiotrophoblast layer in humans, mice, and rats 8-including ribavirin and abacavir. [12][13][14] The fetal distribution of ribavirin was significantly reduced in Ent1-knockout mice at 15 min after administration but no significant difference was seen at 2 h. 13 This may indicate that ENT1 affects the rate, but not the extent, of ribavirin distribution into the fetus, and thus may imply that other transporter proteins contribute to the fetal transfer of ribavirin. Candidate ribavirin transporters include human ENT1, ENT2 (encoded by SLC29A2), CNT2 (encoded by SLC28A2), and CNT3 (encoded by SLC28A3), which were shown to transport ribavirin when expressed in Xenopus oocytes.…”

Section: Introductionmentioning

confidence: 99%

“…8,11 On the other hand, in fresh villous fragments and MVM vesicles of human placenta, nitrobenzylthioinosine (NBMPR) at 0.1 and 100 mM both inhibited the uptake of nucleosides to the same extent, suggesting negligible uptake via ENT2, 12 because nanomolar NBMPR almost completely inhibits ENT1 but has little effect on ENT2, whereas 100 mM NBMPR inhibits ENT2 as well as ENT1. 17 As for CNTs, negligible involvement was suggested based on the Na þ -insensitivity of uptake of nucleosides in human placental MVM vesicles 12,18 and the lack of immunohistochemical detection in CNT proteins at the syncytiotrophoblast layer, 8 but this is in conflict with immunohistochemical detection of CNT1 protein in another study. 11 In the rat placental barrier, the functional expression of ENT2 in placental MVM vesicles was suggested by the observation that adenosine uptake is more potently inhibited by NBMPR at 100 mM than at 0.1 mM, 10 which is inconsistent with the observation in human placental MVMs.…”

Section: Introductionmentioning

confidence: 99%

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Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake

Nishimura

Sano

Takahashi

et al. 2019

Journal of Pharmaceutical Sciences

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The aims of this study are to quantify the protein levels of nucleoside transporters in placental microvillous membranes (MVMs) and to clarify the contributions of these transporters to ribavirin uptake at the placental barrier. Placental MVMs of human and rat expressed equilibrative nucleoside transporter (ENT) 1 protein, whereas the expression of ENT2 protein was obscure. Maternal-to-fetal transfer of [ 3 H] ribavirin in rats was much higher than that of [ 14 C]sucrose. The uptake of [ 3 H]ribavirin by rat placental trophoblast TR-TBT 18 d-1 cells, which functionally express both ENT1 and ENT2 proteins, was saturable, and was significantly inhibited by 0.1 mM nitrobenzylthioinosine, which selectively abolishes ENT1mediated uptake. Dipyridamole at 10 mM is capable of inhibiting ENT2 as well as ENT1, but a degree of inhibition by 10 mM dipyridamole on [ 3 H]ribavirin uptake was not much different from that by 0.1 mM nitrobenzylthioinosine (ENT1-specific inhibitor). Therefore, ENT2 may contribute little to [ 3 H]ribavirin uptake by these cells. Rat ENT1 cRNA-injected oocytes showed increased [ 3 H]ribavirin uptake compared with water-injected oocytes, while rat ENT2 cRNA-injected oocytes did not. In conclusion, ENT1 protein expressed in placental MVMs appears to play a predominant role in the uptake of ribavirin.

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Low oxygen tension differentially regulates the expression of placental solute carriers and ABC transporters

Gorczyca

Bircsak

et al. 2020

FEBS Letters

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Low oxygen concentration, or hypoxia, is an important physiological regulator of placental function including chemical disposition. Here, we compared the ability of low oxygen tension to alter the expression of solute carriers (SLC) and ABC transporters in two human placental models, namely BeWo cells and term placental explants. We found that exposure to low oxygen concentration differentially regulates transporter expression in BeWo cells, including downregulation of ENT1, OATP4A1, OCTN2, BCRP, and MRP2/3/5, and upregulation of CNT1, OAT4, OATP2B1, SERT, SOAT, and MRP1. Similar upregulation of MRP1 and downregulation of MRP5 and BCRP were observed in explants, whereas uptake transporters were decreased or unchanged. Furthermore, a screening of transcriptional regulators of transporters revealed that hypoxia leads to a decrease in the mRNA levels of aryl hydrocarbon receptor, nuclear factor erythroid 2‐related factor 2, and retinoid x receptor alpha in both human placental models. These data suggest that transporter expression is differentially regulated by oxygen concentration across experimental human placental models.

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Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta

Cited by 27 publications

References 60 publications

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake

Low oxygen tension differentially regulates the expression of placental solute carriers and ABC transporters

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