The inhibitory effect of antiretroviral drugs on the L-carnitine uptake in human placenta
Language English Country United States Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
30735677
DOI
10.1016/j.taap.2019.02.002
PII: S0041-008X(19)30043-2
Knihovny.cz E-resources
- Keywords
- Antiretrovirals, Carnitine, Carnitine deficiency, Membrane transport, Placenta,
- MeSH
- Anti-Retroviral Agents toxicity MeSH
- Biological Transport MeSH
- Risk Assessment MeSH
- Carnitine metabolism MeSH
- Humans MeSH
- Maternal Exposure adverse effects MeSH
- Cell Line, Tumor MeSH
- Placenta drug effects metabolism MeSH
- Organic Cation Transport Proteins antagonists & inhibitors metabolism MeSH
- Solute Carrier Family 22 Member 5 antagonists & inhibitors metabolism MeSH
- Symporters MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Anti-Retroviral Agents MeSH
- Carnitine MeSH
- Organic Cation Transport Proteins MeSH
- Solute Carrier Family 22 Member 5 MeSH
- SLC22A4 protein, human MeSH Browser
- SLC22A5 protein, human MeSH Browser
- Symporters 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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