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- Publisher Website: 10.1152/ajpgi.90672.2008
- Scopus: eid_2-s2.0-66149097607
- PMID: 19164483
- WOS: WOS:000264706400026
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Article: Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3
Title | Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3 |
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Authors | |
Keywords | Anti-human immunodeficiency virus drugs Lysosomes Mitochondrial transport |
Issue Date | 2009 |
Publisher | American 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? |
Abstract | human 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 Identifier | http://hdl.handle.net/10722/171381 |
ISSN | 2023 Impact Factor: 3.9 2023 SCImago Journal Rankings: 1.460 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Govindarajan, R | en_US |
dc.contributor.author | Leung, GPH | en_US |
dc.contributor.author | Zhou, M | en_US |
dc.contributor.author | Tse, CM | en_US |
dc.contributor.author | Wang, J | en_US |
dc.contributor.author | Unadkat, JD | en_US |
dc.date.accessioned | 2012-10-30T06:13:45Z | - |
dc.date.available | 2012-10-30T06:13:45Z | - |
dc.date.issued | 2009 | en_US |
dc.identifier.citation | American Journal Of Physiology - Gastrointestinal And Liver Physiology, 2009, v. 296 n. 4, p. G910-G922 | en_US |
dc.identifier.issn | 0193-1857 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171381 | - |
dc.description.abstract | human 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.language | eng | en_US |
dc.publisher | American Physiological Society. The Journal's web site is located at http://intl-ajpgi.physiology.org/ | en_US |
dc.relation.ispartof | American Journal of Physiology - Gastrointestinal and Liver Physiology | en_US |
dc.subject | Anti-human immunodeficiency virus drugs | - |
dc.subject | Lysosomes | - |
dc.subject | Mitochondrial transport | - |
dc.subject.mesh | Antibodies | en_US |
dc.subject.mesh | Antineoplastic Agents - Metabolism | en_US |
dc.subject.mesh | Antiviral Agents - Metabolism | en_US |
dc.subject.mesh | Bacterial Proteins | en_US |
dc.subject.mesh | Cell Line | en_US |
dc.subject.mesh | Epitopes | en_US |
dc.subject.mesh | Female | en_US |
dc.subject.mesh | Gene Silencing | en_US |
dc.subject.mesh | Hepatocytes - Metabolism | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Luminescent Proteins | en_US |
dc.subject.mesh | Mitochondria, Liver - Metabolism | en_US |
dc.subject.mesh | Nucleoside Transport Proteins - Metabolism | en_US |
dc.subject.mesh | Placenta - Metabolism | en_US |
dc.subject.mesh | Rna, Small Interfering | en_US |
dc.subject.mesh | Tissue Culture Techniques | en_US |
dc.title | Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3 | en_US |
dc.type | Article | en_US |
dc.identifier.email | Leung, GPH:gphleung@hkucc.hku.hk | en_US |
dc.identifier.authority | Leung, GPH=rp00234 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1152/ajpgi.90672.2008 | en_US |
dc.identifier.pmid | 19164483 | en_US |
dc.identifier.scopus | eid_2-s2.0-66149097607 | en_US |
dc.identifier.hkuros | 157516 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-66149097607&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 296 | en_US |
dc.identifier.issue | 4 | en_US |
dc.identifier.spage | G910 | en_US |
dc.identifier.epage | G922 | en_US |
dc.identifier.isi | WOS:000264706400026 | - |
dc.publisher.place | United States | en_US |
dc.identifier.f1000 | 1160793 | - |
dc.identifier.scopusauthorid | Govindarajan, R=22979591600 | en_US |
dc.identifier.scopusauthorid | Leung, GPH=35963668200 | en_US |
dc.identifier.scopusauthorid | Zhou, M=14629760500 | en_US |
dc.identifier.scopusauthorid | Tse, CM=7103295076 | en_US |
dc.identifier.scopusauthorid | Wang, J=36119460000 | en_US |
dc.identifier.scopusauthorid | Unadkat, JD=7005150581 | en_US |
dc.identifier.issnl | 0193-1857 | - |