High affinity capture and concentration of quinacrine in polymormonuclear neutrophils via vacuolar ATPase-mediated ion trapping : comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

DC FieldValueLanguage
dc.contributor.authorRoy, Caroline-
dc.contributor.authorGagné, Valérie-
dc.contributor.authorFernandes, Maria J.-
dc.contributor.authorMarceau, François-
dc.date.accessioned2017-11-21T16:15:28Z-
dc.date.available2017-11-21T16:15:28Z-
dc.date.issued2013-04-17-
dc.identifier.issn0041-008Xfr
dc.identifier.urihttp://hdl.handle.net/20.500.11794/15929-
dc.description.abstractMany cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37°C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent KM 1.1 vs. 6.3 µM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at 2.5 µM, 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake Vmax. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes).fr
dc.languageengfr
dc.publisherElsevierfr
dc.subjectQuinacrinefr
dc.subjectPolymorphonuclear leukocytesfr
dc.subjectLymphocytesfr
dc.subjectDrug transportfr
dc.subjectLysosomotropic drugsfr
dc.subjectIon trappingfr
dc.subjectVacuolar ATPasefr
dc.subjectMacroautophagyfr
dc.titleHigh affinity capture and concentration of quinacrine in polymormonuclear neutrophils via vacuolar ATPase-mediated ion trapping : comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugsfr
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherchefr
dcterms.bibliographicCitationToxicology and applied pharmacology, Vol. 270 (2), 77–86 (2013)fr
dc.identifier.doi10.1016/j.taap.2013.04.004fr
dc.identifier.pubmed23603060fr
dc.subject.rvmMépacrinefr
dc.subject.rvmLeucocytesfr
dc.subject.rvmLymphocytesfr
dc.subject.rvmAdénosine-triphosphatasefr
dc.subject.rvmAutophagie (Cytologie)fr
dc.subject.rvmNeutrophilesfr
dc.subject.rvmGranulocytesfr
rioxxterms.versionAccepted Manuscriptfr
rioxxterms.version_of_recordhttps://doi.org/10.1016/j.taap.2013.04.004fr
rioxxterms.project.funder_nameNatural Sciences and Engineering Research Council of Canadafr
rioxxterms.project.funder_nameFonds de Recherche du Québec - Santéfr
bul.rights.periodeEmbargo12 moisfr
Collection:Articles publiés dans des revues avec comité de lecture

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