Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH.

Détails

ID Serval
serval:BIB_6F47958A0A5D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH.
Périodique
Drug metabolism letters
Auteur(s)
Mettral J.B., Faller N., Cruchon S., Sottas L., Buclin T., Schild L., Choong E., Nahimana A., Decosterd L.A.
ISSN
1874-0758 (Electronic)
ISSN-L
1872-3128
Statut éditorial
Publié
Date de publication
2019
Peer-reviewed
Oui
Volume
13
Numéro
2
Pages
102-110
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment.
To determine the functional contribution of OCTs and extracellular pH on imatinib cellular disposition.
We measured imatinib uptake in two different models of selective OCTs drug transporter expression (transfected Xenopus laevis oocytes and OCT-expressing HEK293 human cells), incubated at pH 7.4 and 6, using specific mass spectrometry analysis.
Imatinib cellular uptake occurred independently of OCT1- OCT2- or OCT3-mediated drug transport at pH 7.4. Uptake of the OCTs substrate tetraethylammonium in oocytes remained intact at pH 6, while the accumulation of imatinib in oocytes was 10-fold lower than at pH 7.4, irrespectively of OCTs expressions. In OCT1- and OCT2-HEK cells at pH 6, imatinib accumulation was reduced by 2- 3-fold regardless of OCTs expressions. Since 99.5% of imatinib at pH6 is under the cationic form, the reduced cellular accumulation of imatinib at such pH may be explained by the lower amount of uncharged imatinib remaining for passive diffusion across cellular membrane.
Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment.
Mots-clé
Imatinib, MATE1, OCT1, OCT2, OCT3, acidic extracellular pH, cellular concentrations, chronic myeloid leukemia, influx organic cation transporters, mass spectrometry., multidrug and toxin extrusion protein 1, mass spectrometry, multidrug and toxin extrusion protein 1.
Pubmed
Création de la notice
25/03/2019 10:28
Dernière modification de la notice
05/02/2020 6:19
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