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

Many 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 catio...

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Veröffentlicht in:Toxicology and applied pharmacology 2013-07, Vol.270 (2), p.77-86
Hauptverfasser: Roy, Caroline, Gagné, Valérie, Fernandes, Maria J.G., Marceau, François
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Gagné, Valérie
Fernandes, Maria J.G.
Marceau, François
description Many 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. 6.3μM, 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 ≥2.5μM, ≥2h). 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). [Display omitted] •Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping.•Human peripheral blood leukocytes capture and concentrate quinacrine.•Polymorphonuclear leukocytes do so with higher apparent affinity.•Polymorphonuclear are also more competent than lymphocytes for pinocytosis.
doi_str_mv 10.1016/j.taap.2013.04.004
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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. 6.3μM, 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 ≥2.5μM, ≥2h). 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). [Display omitted] •Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping.•Human peripheral blood leukocytes capture and concentrate quinacrine.•Polymorphonuclear leukocytes do so with higher apparent affinity.•Polymorphonuclear are also more competent than lymphocytes for pinocytosis.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2013.04.004</identifier><identifier>PMID: 23603060</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; AFFINITY ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiparasitic agents ; Autophagy - drug effects ; Biological and medical sciences ; Enzyme Inhibitors - blood ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Humans ; Immunoblotting ; Ion trapping ; Kinetics ; Leukocytes - enzymology ; Leukocytes - metabolism ; LYMPHOCYTES ; Macroautophagy ; Macrolides - blood ; Macrolides - pharmacology ; Medical sciences ; Microscopy, Fluorescence ; MONOCYTES ; NEUTROPHILS ; Neutrophils - enzymology ; Neutrophils - metabolism ; PHAGOCYTES ; Pharmacology. Drug treatments ; Pinocytosis - physiology ; Polymorphonuclear leukocytes ; Quinacrine ; Quinacrine - blood ; Regression Analysis ; TOXICITY ; Toxicology ; TRAPPING ; UPTAKE ; Vacuolar ATPase ; Vacuolar Proton-Translocating ATPases - antagonists &amp; inhibitors ; Vacuolar Proton-Translocating ATPases - blood</subject><ispartof>Toxicology and applied pharmacology, 2013-07, Vol.270 (2), p.77-86</ispartof><rights>2013 Elsevier Inc.</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2013 Elsevier Inc. 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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. 6.3μM, 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 ≥2.5μM, ≥2h). 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). [Display omitted] •Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping.•Human peripheral blood leukocytes capture and concentrate quinacrine.•Polymorphonuclear leukocytes do so with higher apparent affinity.•Polymorphonuclear are also more competent than lymphocytes for pinocytosis.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>AFFINITY</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiparasitic agents</subject><subject>Autophagy - drug effects</subject><subject>Biological and medical sciences</subject><subject>Enzyme Inhibitors - blood</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Ion trapping</subject><subject>Kinetics</subject><subject>Leukocytes - enzymology</subject><subject>Leukocytes - metabolism</subject><subject>LYMPHOCYTES</subject><subject>Macroautophagy</subject><subject>Macrolides - blood</subject><subject>Macrolides - pharmacology</subject><subject>Medical sciences</subject><subject>Microscopy, Fluorescence</subject><subject>MONOCYTES</subject><subject>NEUTROPHILS</subject><subject>Neutrophils - enzymology</subject><subject>Neutrophils - metabolism</subject><subject>PHAGOCYTES</subject><subject>Pharmacology. Drug treatments</subject><subject>Pinocytosis - physiology</subject><subject>Polymorphonuclear leukocytes</subject><subject>Quinacrine</subject><subject>Quinacrine - blood</subject><subject>Regression Analysis</subject><subject>TOXICITY</subject><subject>Toxicology</subject><subject>TRAPPING</subject><subject>UPTAKE</subject><subject>Vacuolar ATPase</subject><subject>Vacuolar Proton-Translocating ATPases - antagonists &amp; inhibitors</subject><subject>Vacuolar Proton-Translocating ATPases - blood</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uk2P0zAQjRCILQt_gAOyhJC4pDhxmg_EZVUBi7QSHBaJm-U442aKY3ttp6i_mT-Bs-3CjZMtz3vPb2Zelr0s6LqgRf1uv45CuHVJC7am1ZrS6lG2KmhX55Qx9jhbpZcip7T9cZE9C2FPKe2qqniaXZSspozWdJX9vsbdSIRSaDAeiRQuzh6IMAOR1kgw0YuI1hCryN2MRkiPBgga4qw-Tta70ZpZahCeGJijt25EHcgBBTkIOVudCle330SAfIIBRYSBLHpJ1zk0u_dkaycnPIb0-AvjSGwcwRMHHl26CE16be1ANMw_rTxGCPfucHIa5b23QJT1JLHIgCF67OcHx6c6SjL4eReeZ0-U0AFenM_L7Punj7fb6_zm6-cv26ubXFZVE_MCZNkzpnqq6oHJQlQUNo1oC6Y6aKWStNt0NZNNzbquahhVVU2BJfLQbkrRs8vs9UnXhog8SIwgxzRNAzLysizbTVpPQr09oZy3dzOEyCcMErQWBuwceFGXTde2aX0JWp6g0tsQPCjuPE7CH3lB-RIFvudLFPgSBU4rnhafSK_O-nOfJv-X8rD7BHhzBogghVZeGInhH66pWEc3y-8fTjhIMzsg-KUlSNkY0C8dDRb_5-MPOo3ZIQ</recordid><startdate>20130715</startdate><enddate>20130715</enddate><creator>Roy, Caroline</creator><creator>Gagné, Valérie</creator><creator>Fernandes, Maria J.G.</creator><creator>Marceau, François</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7U7</scope><scope>C1K</scope><scope>SOI</scope><scope>OTOTI</scope></search><sort><creationdate>20130715</creationdate><title>High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs</title><author>Roy, Caroline ; Gagné, Valérie ; Fernandes, Maria J.G. ; Marceau, François</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-1ec2b33fb0f6d3c1a40e57a813f9e8cfc095963c763994730f460e3c44d852ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>AFFINITY</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiparasitic agents</topic><topic>Autophagy - drug effects</topic><topic>Biological and medical sciences</topic><topic>Enzyme Inhibitors - blood</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Ion trapping</topic><topic>Kinetics</topic><topic>Leukocytes - enzymology</topic><topic>Leukocytes - metabolism</topic><topic>LYMPHOCYTES</topic><topic>Macroautophagy</topic><topic>Macrolides - blood</topic><topic>Macrolides - pharmacology</topic><topic>Medical sciences</topic><topic>Microscopy, Fluorescence</topic><topic>MONOCYTES</topic><topic>NEUTROPHILS</topic><topic>Neutrophils - enzymology</topic><topic>Neutrophils - metabolism</topic><topic>PHAGOCYTES</topic><topic>Pharmacology. Drug treatments</topic><topic>Pinocytosis - physiology</topic><topic>Polymorphonuclear leukocytes</topic><topic>Quinacrine</topic><topic>Quinacrine - blood</topic><topic>Regression Analysis</topic><topic>TOXICITY</topic><topic>Toxicology</topic><topic>TRAPPING</topic><topic>UPTAKE</topic><topic>Vacuolar ATPase</topic><topic>Vacuolar Proton-Translocating ATPases - antagonists &amp; inhibitors</topic><topic>Vacuolar Proton-Translocating ATPases - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Roy, Caroline</creatorcontrib><creatorcontrib>Gagné, Valérie</creatorcontrib><creatorcontrib>Fernandes, Maria J.G.</creatorcontrib><creatorcontrib>Marceau, François</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><collection>OSTI.GOV</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roy, Caroline</au><au>Gagné, Valérie</au><au>Fernandes, Maria J.G.</au><au>Marceau, François</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2013-07-15</date><risdate>2013</risdate><volume>270</volume><issue>2</issue><spage>77</spage><epage>86</epage><pages>77-86</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Many 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. 6.3μM, 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 ≥2.5μM, ≥2h). 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). [Display omitted] •Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping.•Human peripheral blood leukocytes capture and concentrate quinacrine.•Polymorphonuclear leukocytes do so with higher apparent affinity.•Polymorphonuclear are also more competent than lymphocytes for pinocytosis.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>23603060</pmid><doi>10.1016/j.taap.2013.04.004</doi><tpages>10</tpages></addata></record>
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language eng
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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects 60 APPLIED LIFE SCIENCES
AFFINITY
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiparasitic agents
Autophagy - drug effects
Biological and medical sciences
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Immunoblotting
Ion trapping
Kinetics
Leukocytes - enzymology
Leukocytes - metabolism
LYMPHOCYTES
Macroautophagy
Macrolides - blood
Macrolides - pharmacology
Medical sciences
Microscopy, Fluorescence
MONOCYTES
NEUTROPHILS
Neutrophils - enzymology
Neutrophils - metabolism
PHAGOCYTES
Pharmacology. Drug treatments
Pinocytosis - physiology
Polymorphonuclear leukocytes
Quinacrine
Quinacrine - blood
Regression Analysis
TOXICITY
Toxicology
TRAPPING
UPTAKE
Vacuolar ATPase
Vacuolar Proton-Translocating ATPases - antagonists & inhibitors
Vacuolar Proton-Translocating ATPases - blood
title High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs
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