The inhibitory effect of antiretroviral drugs on the L-carnitine uptake in human placenta
Autor: | Frantisek Staud, Rona Karahoda, Martina Ceckova |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Efavirenz Organic Cation Transport Proteins Placenta viruses Pharmacology Toxicology Risk Assessment Carnitine transport 03 medical and health sciences chemistry.chemical_compound Zidovudine 0302 clinical medicine Pregnancy Carnitine Cell Line Tumor medicine Humans Solute Carrier Family 22 Member 5 Symporters business.industry virus diseases Biological Transport Lopinavir biochemical phenomena metabolism and nutrition Raltegravir Atazanavir 030104 developmental biology Anti-Retroviral Agents chemistry Maternal Exposure 030220 oncology & carcinogenesis Female Ritonavir business Saquinavir medicine.drug |
Zdroj: | Toxicology and Applied Pharmacology. 368:18-25 |
ISSN: | 0041-008X |
Popis: | 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. |
Databáze: | OpenAIRE |
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