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Article: Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3

TitleFacilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3
Authors
Issue Date2009
PublisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpgi.physiology.org/
Citation
American Journal Of Physiology - Gastrointestinal And Liver Physiology, 2009, v. 296 n. 4, p. G910-G922 How to Cite?
Abstracthuman equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified a substantial presence of hENT3 in the mitochondria, with additional presence at the cell surface of two placental cell lines (JAR, JEG3). Mitochondrial or cell surface hENT3 expression was confirmed in human hepatocytes and placental tissues, respectively. Unlike endogenous hENT3, yellow fluorescent protein (YFP)-tagged hENT3 was partially directed to the lysosomes. Xenopus oocytes expressing NH2-terminal-deleted hENT3 (expressed at the cell surface) showed pH-dependent interaction with several classes of nucleosides (anti-HIV ddNs, gemcitabine, fialuridine, ribavirin) that produce mitochondrial toxicity. Transport studies in hENT3 gene-silenced JAR cells showed significant reduction in mitochondrial transport of nucleosides and nucleoside drugs. Our data suggest that cellular localization of hENT3 is cell type dependent and the native transporter is substantially expressed in mitochondria and/or cell surface. hENT3-mediated mitochondrial transport may play an important role in mediating clinically observed mitochondrial toxicity of nucleoside drugs. In addition, our finding that hENT3 is a mitochondrial transporter is consistent with the recent finding that mutations in the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome. Copyright © 2009 the American Physiological Society.
Persistent Identifierhttp://hdl.handle.net/10722/171381
ISSN
2015 Impact Factor: 3.297
2015 SCImago Journal Rankings: 1.936
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGovindarajan, Ren_US
dc.contributor.authorLeung, GPHen_US
dc.contributor.authorZhou, Men_US
dc.contributor.authorTse, CMen_US
dc.contributor.authorWang, Jen_US
dc.contributor.authorUnadkat, JDen_US
dc.date.accessioned2012-10-30T06:13:45Z-
dc.date.available2012-10-30T06:13:45Z-
dc.date.issued2009en_US
dc.identifier.citationAmerican Journal Of Physiology - Gastrointestinal And Liver Physiology, 2009, v. 296 n. 4, p. G910-G922en_US
dc.identifier.issn0193-1857en_US
dc.identifier.urihttp://hdl.handle.net/10722/171381-
dc.description.abstracthuman equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified a substantial presence of hENT3 in the mitochondria, with additional presence at the cell surface of two placental cell lines (JAR, JEG3). Mitochondrial or cell surface hENT3 expression was confirmed in human hepatocytes and placental tissues, respectively. Unlike endogenous hENT3, yellow fluorescent protein (YFP)-tagged hENT3 was partially directed to the lysosomes. Xenopus oocytes expressing NH2-terminal-deleted hENT3 (expressed at the cell surface) showed pH-dependent interaction with several classes of nucleosides (anti-HIV ddNs, gemcitabine, fialuridine, ribavirin) that produce mitochondrial toxicity. Transport studies in hENT3 gene-silenced JAR cells showed significant reduction in mitochondrial transport of nucleosides and nucleoside drugs. Our data suggest that cellular localization of hENT3 is cell type dependent and the native transporter is substantially expressed in mitochondria and/or cell surface. hENT3-mediated mitochondrial transport may play an important role in mediating clinically observed mitochondrial toxicity of nucleoside drugs. In addition, our finding that hENT3 is a mitochondrial transporter is consistent with the recent finding that mutations in the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome. Copyright © 2009 the American Physiological Society.en_US
dc.languageengen_US
dc.publisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpgi.physiology.org/en_US
dc.relation.ispartofAmerican Journal of Physiology - Gastrointestinal and Liver Physiologyen_US
dc.subject.meshAntibodiesen_US
dc.subject.meshAntineoplastic Agents - Metabolismen_US
dc.subject.meshAntiviral Agents - Metabolismen_US
dc.subject.meshBacterial Proteinsen_US
dc.subject.meshCell Lineen_US
dc.subject.meshEpitopesen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Silencingen_US
dc.subject.meshHepatocytes - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshLuminescent Proteinsen_US
dc.subject.meshMitochondria, Liver - Metabolismen_US
dc.subject.meshNucleoside Transport Proteins - Metabolismen_US
dc.subject.meshPlacenta - Metabolismen_US
dc.subject.meshRna, Small Interferingen_US
dc.subject.meshTissue Culture Techniquesen_US
dc.titleFacilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3en_US
dc.typeArticleen_US
dc.identifier.emailLeung, GPH:gphleung@hkucc.hku.hken_US
dc.identifier.authorityLeung, GPH=rp00234en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1152/ajpgi.90672.2008en_US
dc.identifier.pmid19164483en_US
dc.identifier.scopuseid_2-s2.0-66149097607en_US
dc.identifier.hkuros157516-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66149097607&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume296en_US
dc.identifier.issue4en_US
dc.identifier.spageG910en_US
dc.identifier.epageG922en_US
dc.identifier.isiWOS:000264706400026-
dc.publisher.placeUnited Statesen_US
dc.identifier.f10001160793-
dc.identifier.scopusauthoridGovindarajan, R=22979591600en_US
dc.identifier.scopusauthoridLeung, GPH=35963668200en_US
dc.identifier.scopusauthoridZhou, M=14629760500en_US
dc.identifier.scopusauthoridTse, CM=7103295076en_US
dc.identifier.scopusauthoridWang, J=36119460000en_US
dc.identifier.scopusauthoridUnadkat, JD=7005150581en_US

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