E-viri
Recenzirano
-
Minuesa, Gerard; Volk, Christopher; Molina-Arcas, Míriam; Gorboulev, Valentin; Erkizia, Itziar; Arndt, Petra; Clotet, Bonaventura; Pastor-Anglada, Marçal; Koepsell, Hermann; Martinez-Picado, Javier
The Journal of pharmacology and experimental therapeutics 329, Številka: 1Journal Article
Nucleoside reverse transcriptase inhibitors (NRTIs) need to enter cells to act against the HIV-1. Human organic cation transporters (hOCT1-3) are expressed and active in CD4+ T cells, the main target of HIV-1, and have been associated with antiviral uptake in different tissues. In this study, we examined whether NRTIs interact and are substrates of hOCT in cells stably expressing these transporters. Using (3)HN-methyl-4-phenylpyridinium, we found a high-affinity interaction among abacavir (1S,4R)-4-2-amino-6-(cyclopropylamino)purin-9-yl-cyclopent-2-enylmethanol sulfate (ABC); <0.08 nM, azidothymidine 3'-azido-3'-deoxythymidine (AZT); <0.4 nM, tenofovir disoproxil fumarate (<1.0 nM), and emtricitabine (<2.5 nM) and hOCTs. Using a wide range of concentrations of lamivudine (-)-beta-L-2',3'-dideoxy-3'-thiacyitidine (3TC), we determined two different binding sites for hOCTs: a high-affinity site (K(d1) = 12.3-15.4 pM) and a low-affinity site (K(d2) = 1.9-3.4 mM). Measuring direct uptake of (3)H3TC and inhibition with hOCT substrates, we identified 3TC as a novel substrate for hOCT1, 2, and 3, with hOCT1 as the most efficient transporter (K(m) = 1.25 +/- 0.1 mM; V(max) = 10.40 +/- 0.32 nmol/mg protein/min; V(max)/K(m) = 8.32 +/- 0.40 microl/mg protein/min). In drug-drug interaction experiments, we analyzed cis-inhibition of (3)H3TC uptake by ABC and AZT and found that 40 to 50% was inhibited at low concentrations of the drugs (K(i) = 22-500 pM). These data reveal that NRTIs experience a high-affinity interaction with hOCTs, suggesting a putative role for these drugs as modulators of hOCT activity. Finally, 3TC is a novel substrate for hOCTs and the inhibition of its uptake at low concentrations of ABC and AZT could have implications for the pharmacokinetics of 3TC.
![loading ... loading ...](themes/default/img/ajax-loading.gif)
Vnos na polico
Trajna povezava
- URL:
Faktor vpliva
Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
---|---|---|---|---|---|---|---|---|
JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Baze podatkov, v katerih je revija indeksirana
Ime baze podatkov | Področje | Leto |
---|
Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
---|
Vir: Osebne bibliografije
in: SICRIS
To gradivo vam je dostopno v celotnem besedilu. Če kljub temu želite naročiti gradivo, kliknite gumb Nadaljuj.