Nucleoside transporter subtype expression: effects on potency of adenosine kinase inhibitors.
Identifieur interne : 003112 ( Main/Exploration ); précédent : 003111; suivant : 003113Nucleoside transporter subtype expression: effects on potency of adenosine kinase inhibitors.
Auteurs : C J Sinclair [Canada] ; A E Powell ; W. Xiong ; C G Larivière ; S A Baldwin ; C E Cass ; J D Young ; F E ParkinsonSource :
- British journal of pharmacology [ 0007-1188 ] ; 2001.
English descriptors
- KwdEn :
- Adenine Nucleotides (metabolism), Adenosine (pharmacokinetics), Adenosine Kinase (antagonists & inhibitors), Animals, Carrier Proteins (antagonists & inhibitors), Carrier Proteins (genetics), Carrier Proteins (physiology), Deoxyadenosines (pharmacology), Dose-Response Relationship, Drug, Enzyme Inhibitors (pharmacology), Equilibrative Nucleoside Transport Proteins, Equilibrative Nucleoside Transporter 1, Equilibrative-Nucleoside Transporter 2, Gene Expression, Membrane Proteins (antagonists & inhibitors), Membrane Proteins (genetics), Membrane Proteins (physiology), Membrane Transport Proteins (genetics), Membrane Transport Proteins (physiology), Nucleoside Transport Proteins, Thioinosine (analogs & derivatives), Thioinosine (pharmacology), Tritium, Tubercidin (analogs & derivatives), Tubercidin (pharmacology), Tumor Cells, Cultured (drug effects), Tumor Cells, Cultured (metabolism).
- MESH :
- chemical , analogs & derivatives : Thioinosine, Tubercidin.
- chemical , antagonists & inhibitors : Adenosine Kinase, Carrier Proteins, Membrane Proteins.
- chemical , genetics : Carrier Proteins, Membrane Proteins, Membrane Transport Proteins.
- chemical , metabolism : Adenine Nucleotides.
- chemical , pharmacokinetics : Adenosine.
- chemical , pharmacology : Deoxyadenosines, Enzyme Inhibitors, Thioinosine, Tubercidin.
- chemical , physiology : Carrier Proteins, Membrane Proteins, Membrane Transport Proteins.
- drug effects : Tumor Cells, Cultured.
- metabolism : Tumor Cells, Cultured.
- Animals, Dose-Response Relationship, Drug, Equilibrative Nucleoside Transport Proteins, Equilibrative Nucleoside Transporter 1, Equilibrative-Nucleoside Transporter 2, Gene Expression, Nucleoside Transport Proteins, Tritium.
Abstract
1. Adenosine kinase (AK) inhibitors can enhance adenosine levels and potentiate adenosine receptor activation. As the AK inhibitors 5' iodotubercidin (ITU) and 5-amino-5'-deoxyadenosine (NH(2)dAdo) are nucleoside analogues, we hypothesized that nucleoside transporter subtype expression can affect the potency of these inhibitors in intact cells. 3. Three nucleoside transporter subtypes that mediate adenosine permeation of rat cells have been characterized and cloned: equilibrative transporters rENT1 and rENT2 and concentrative transporter rCNT2. We stably transfected rat C6 glioma cells, which express rENT2 nucleoside transporters, with rENT1 (rENT1-C6 cells) or rCNT2 (rCNT2-C6 cells) nucleoside transporters. 3. We tested the effects of ITU and NH(2)dAdo on [(3)H]-adenosine uptake and conversion to [(3)H]-adenine nucleotides in the three cell types. NH(2)dAdo did not show any cell type selectivity. In contrast, ITU showed significant inhibition of [(3)H]-adenosine uptake and [(3)H]-adenine nucleotide formation at concentrations < or =100 nM in rENT1-C6 cells, while concentrations > or =3 microM were required for C6 or rCNT2-C6 cells. 4. Nitrobenzylthioinosine (NBMPR; 100 nM), a selective inhibitor of rENT1, abolished the effects of nanomolar concentrations of ITU in rENT1-C6 cells. 5. This study demonstrates that the effects of ITU, but not NH(2)dAdo, in whole cell assays are dependent upon nucleoside transporter subtype expression. Thus, cellular and tissue differences in expression of nucleoside transporter subtypes may affect the pharmacological actions of some AK inhibitors.
DOI: 10.1038/sj.bjp.0704349
PubMed: 11682452
Affiliations:
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Le document en format XML
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Xiong</name></author><author><name sortKey="Lariviere, C G" sort="Lariviere, C G" uniqKey="Lariviere C" first="C G" last="Larivière">C G Larivière</name></author><author><name sortKey="Baldwin, S A" sort="Baldwin, S A" uniqKey="Baldwin S" first="S A" last="Baldwin">S A Baldwin</name></author><author><name sortKey="Cass, C E" sort="Cass, C E" uniqKey="Cass C" first="C E" last="Cass">C E Cass</name></author><author><name sortKey="Young, J D" sort="Young, J D" uniqKey="Young J" first="J D" last="Young">J D Young</name></author><author><name sortKey="Parkinson, F E" sort="Parkinson, F E" uniqKey="Parkinson F" first="F E" last="Parkinson">F E Parkinson</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2001">2001</date><idno type="RBID">pubmed:11682452</idno><idno type="pmid">11682452</idno><idno type="doi">10.1038/sj.bjp.0704349</idno><idno type="wicri:Area/PubMed/Corpus">001549</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001549</idno><idno type="wicri:Area/PubMed/Curation">001549</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001549</idno><idno type="wicri:Area/PubMed/Checkpoint">001549</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001549</idno><idno type="wicri:Area/Ncbi/Merge">000192</idno><idno type="wicri:Area/Ncbi/Curation">000192</idno><idno type="wicri:Area/Ncbi/Checkpoint">000192</idno><idno type="wicri:doubleKey">0007-1188:2001:Sinclair C:nucleoside:transporter:subtype</idno><idno type="wicri:Area/Main/Merge">003569</idno><idno type="wicri:Area/Main/Curation">003112</idno><idno type="wicri:Area/Main/Exploration">003112</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Nucleoside transporter subtype expression: effects on potency of adenosine kinase inhibitors.</title><author><name sortKey="Sinclair, C J" sort="Sinclair, C J" uniqKey="Sinclair C" first="C J" last="Sinclair">C J Sinclair</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author><author><name sortKey="Powell, A E" sort="Powell, A E" uniqKey="Powell A" first="A E" last="Powell">A E Powell</name></author><author><name sortKey="Xiong, W" sort="Xiong, W" uniqKey="Xiong W" first="W" last="Xiong">W. Xiong</name></author><author><name sortKey="Lariviere, C G" sort="Lariviere, C G" uniqKey="Lariviere C" first="C G" last="Larivière">C G Larivière</name></author><author><name sortKey="Baldwin, S A" sort="Baldwin, S A" uniqKey="Baldwin S" first="S A" last="Baldwin">S A Baldwin</name></author><author><name sortKey="Cass, C E" sort="Cass, C E" uniqKey="Cass C" first="C E" last="Cass">C E Cass</name></author><author><name sortKey="Young, J D" sort="Young, J D" uniqKey="Young J" first="J D" last="Young">J D Young</name></author><author><name sortKey="Parkinson, F E" sort="Parkinson, F E" uniqKey="Parkinson F" first="F E" last="Parkinson">F E Parkinson</name></author></analytic><series><title level="j">British journal of pharmacology</title><idno type="ISSN">0007-1188</idno><imprint><date when="2001" type="published">2001</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenine Nucleotides (metabolism)</term><term>Adenosine (pharmacokinetics)</term><term>Adenosine Kinase (antagonists & inhibitors)</term><term>Animals</term><term>Carrier Proteins (antagonists & inhibitors)</term><term>Carrier Proteins (genetics)</term><term>Carrier Proteins (physiology)</term><term>Deoxyadenosines (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Enzyme Inhibitors (pharmacology)</term><term>Equilibrative Nucleoside Transport Proteins</term><term>Equilibrative Nucleoside Transporter 1</term><term>Equilibrative-Nucleoside Transporter 2</term><term>Gene Expression</term><term>Membrane Proteins (antagonists & inhibitors)</term><term>Membrane Proteins (genetics)</term><term>Membrane Proteins (physiology)</term><term>Membrane Transport Proteins (genetics)</term><term>Membrane Transport Proteins (physiology)</term><term>Nucleoside Transport Proteins</term><term>Thioinosine (analogs & derivatives)</term><term>Thioinosine (pharmacology)</term><term>Tritium</term><term>Tubercidin (analogs & derivatives)</term><term>Tubercidin (pharmacology)</term><term>Tumor Cells, Cultured (drug effects)</term><term>Tumor Cells, Cultured (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Thioinosine</term><term>Tubercidin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Adenosine Kinase</term><term>Carrier Proteins</term><term>Membrane Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Carrier Proteins</term><term>Membrane Proteins</term><term>Membrane Transport Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenine Nucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Adenosine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Deoxyadenosines</term><term>Enzyme Inhibitors</term><term>Thioinosine</term><term>Tubercidin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Carrier Proteins</term><term>Membrane Proteins</term><term>Membrane Transport Proteins</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Equilibrative Nucleoside Transport Proteins</term><term>Equilibrative Nucleoside Transporter 1</term><term>Equilibrative-Nucleoside Transporter 2</term><term>Gene Expression</term><term>Nucleoside Transport Proteins</term><term>Tritium</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">1. Adenosine kinase (AK) inhibitors can enhance adenosine levels and potentiate adenosine receptor activation. As the AK inhibitors 5' iodotubercidin (ITU) and 5-amino-5'-deoxyadenosine (NH(2)dAdo) are nucleoside analogues, we hypothesized that nucleoside transporter subtype expression can affect the potency of these inhibitors in intact cells. 3. Three nucleoside transporter subtypes that mediate adenosine permeation of rat cells have been characterized and cloned: equilibrative transporters rENT1 and rENT2 and concentrative transporter rCNT2. We stably transfected rat C6 glioma cells, which express rENT2 nucleoside transporters, with rENT1 (rENT1-C6 cells) or rCNT2 (rCNT2-C6 cells) nucleoside transporters. 3. We tested the effects of ITU and NH(2)dAdo on [(3)H]-adenosine uptake and conversion to [(3)H]-adenine nucleotides in the three cell types. NH(2)dAdo did not show any cell type selectivity. In contrast, ITU showed significant inhibition of [(3)H]-adenosine uptake and [(3)H]-adenine nucleotide formation at concentrations < or =100 nM in rENT1-C6 cells, while concentrations > or =3 microM were required for C6 or rCNT2-C6 cells. 4. Nitrobenzylthioinosine (NBMPR; 100 nM), a selective inhibitor of rENT1, abolished the effects of nanomolar concentrations of ITU in rENT1-C6 cells. 5. This study demonstrates that the effects of ITU, but not NH(2)dAdo, in whole cell assays are dependent upon nucleoside transporter subtype expression. Thus, cellular and tissue differences in expression of nucleoside transporter subtypes may affect the pharmacological actions of some AK inhibitors.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Manitoba</li></region><settlement><li>Winnipeg</li></settlement><orgName><li>Université du Manitoba</li></orgName></list><tree><noCountry><name sortKey="Baldwin, S A" sort="Baldwin, S A" uniqKey="Baldwin S" first="S A" last="Baldwin">S A Baldwin</name><name sortKey="Cass, C E" sort="Cass, C E" uniqKey="Cass C" first="C E" last="Cass">C E Cass</name><name sortKey="Lariviere, C G" sort="Lariviere, C G" uniqKey="Lariviere C" first="C G" last="Larivière">C G Larivière</name><name sortKey="Parkinson, F E" sort="Parkinson, F E" uniqKey="Parkinson F" first="F E" last="Parkinson">F E Parkinson</name><name sortKey="Powell, A E" sort="Powell, A E" uniqKey="Powell A" first="A E" last="Powell">A E Powell</name><name sortKey="Xiong, W" sort="Xiong, W" uniqKey="Xiong W" first="W" last="Xiong">W. Xiong</name><name sortKey="Young, J D" sort="Young, J D" uniqKey="Young J" first="J D" last="Young">J D Young</name></noCountry><country name="Canada"><region name="Manitoba"><name sortKey="Sinclair, C J" sort="Sinclair, C J" uniqKey="Sinclair C" first="C J" last="Sinclair">C J Sinclair</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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