Equilibrative nucleoside transporter 1 (ENT1, SLC29A1) facilitates transfer of the antiretroviral drug abacavir across the placenta
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10382889" target="_blank" >RIV/00216208:11160/18:10382889 - isvavai.cz</a>
Result on the web
<a href="http://dmd.aspetjournals.org/content/46/11/1817" target="_blank" >http://dmd.aspetjournals.org/content/46/11/1817</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1124/dmd.118.083329" target="_blank" >10.1124/dmd.118.083329</a>
Alternative languages
Result language
angličtina
Original language name
Equilibrative nucleoside transporter 1 (ENT1, SLC29A1) facilitates transfer of the antiretroviral drug abacavir across the placenta
Original language description
Abacavir is a preferred antiretroviral drug for preventing mother-tochild human immunodeficiency virus transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, equilibrative nucleoside transporters (ENTs, SLC29A) and/or Na+-dependent concentrative nucleoside transporters (CNTs, SLC28A), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using the choriocarcinoma-derived BeWo cell line, human fresh villous fragments, and microvillous plasma membrane (MVM) vesicles. Using endogenous substrates of nucleoside transporters, [3H]-adenosine (ENTs, CNT2, and CNT3) and [3H]-thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells, whereas experiments in the villous fragments and MVM vesicles, representing a model of the apical membrane of a syncytiotrophoblast, revealed only ENT1 activity. When testing [3H]-abacavir uptakes, we showed that of the nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na+-dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [3H]-abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable interindividual variability in their expression. Therefore, drug-drug interactions and the effect of interindividual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/GA17-16169S" target="_blank" >GA17-16169S: In vitro, in situ and ex vivo study of interactions of novel antiviral agents with drug transporters; effect on their passage across the placenta</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Drug Metabolism and Disposition
ISSN
0090-9556
e-ISSN
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Volume of the periodical
46
Issue of the periodical within the volume
11
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
1817-1826
UT code for WoS article
000452484200038
EID of the result in the Scopus database
2-s2.0-85055079674