The inhibitory effect of antiretroviral drugs on the L-carnitine uptake in human placenta
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu srovnávací studie, časopisecké články, práce podpořená grantem
PubMed
30735677
DOI
10.1016/j.taap.2019.02.002
PII: S0041-008X(19)30043-2
Knihovny.cz E-zdroje
- Klíčová slova
- Antiretrovirals, Carnitine, Carnitine deficiency, Membrane transport, Placenta,
- MeSH
- antiretrovirové látky toxicita MeSH
- biologický transport MeSH
- hodnocení rizik MeSH
- karnitin metabolismus MeSH
- lidé MeSH
- matka - expozice noxám škodlivé účinky MeSH
- nádorové buněčné linie MeSH
- placenta účinky léků metabolismus MeSH
- proteiny přenášející organické kationty antagonisté a inhibitory metabolismus MeSH
- rodina nosičů rozpuštěných látek 22, člen 5 antagonisté a inhibitory metabolismus MeSH
- symportéry MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- antiretrovirové látky MeSH
- karnitin MeSH
- proteiny přenášející organické kationty MeSH
- rodina nosičů rozpuštěných látek 22, člen 5 MeSH
- SLC22A4 protein, human MeSH Prohlížeč
- SLC22A5 protein, human MeSH Prohlížeč
- symportéry MeSH
In spite of remarkable reduction in the number of children born with HIV due to antiretroviral therapy, concerns remain on the short- and long-term effects of antiretroviral drugs at the feto-placental unit. Cardio- and skeletal myopathies have been reported in children exposed to antiretroviral drugs prenatally. These conditions have also been described in perturbed placental transfer of l-carnitine, an essential co-factor in fatty acid oxidation. Due to limited fetal and placental synthesis, carnitine supply is maintained through the placental carnitine uptake from maternal blood by the organic cation/carnitine transporters OCTN1 and OCTN2 (SLC22A4 and SLC22A5, respectively). The aim of our study was to investigate potential inhibition of placental carnitine uptake by a broad range of antiretroviral drugs comprising nucleoside/nucleotide reverse transcriptase inhibitors (lamivudine, zidovudine, abacavir, tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (rilpivirine, efavirenz, etravirine), protease inhibitors (ritonavir, lopinavir, atazanavir, saquinavir, tipranavir), integrase inhibitors (raltegravir, dolutegravir, elvitegravir) and viral entry inhibitor, maraviroc. Studies in choriocarcinoma BeWo cells and human placenta-derived models confirmed predominant expression and function of OCTN2 above OCTN1 in l-carnitine transport. Subsequent screenings in BeWo cells and isolated MVM vesicles revealed seven antiretroviral drugs as inhibitors of the Na+-dependent l-carnitine uptake, corresponding to OCTN2. Ritonavir, saquinavir and elvitegravir showed the highest inhibitory potential which was further confirmed for ritonavir and saquinavir in placental fresh villous fragments. Our data indicate possible impairment in placental and fetal supply of l-carnitine with ritonavir and saquinavir, while suggesting retained placental carnitine transport with the other antiretroviral drugs.
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