Bilirubin Protects Astrocytes from Its Own Toxicity by Inducing Up-Regulation and Translocation of Multidrug Resistance-Associated Protein 1 (Mrp1)
Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of o...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2004-02, Vol.101 (8), p.2470-2475 |
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| creator | Gennuso, Florinda Fernetti, Cristina Tirolo, Cataldo Testa, Nuccio L'Episcopo, Francesca Caniglia, Salvo Morale, Maria Concetta Ostrow, J. Donald Pascolo, Lorella Tiribelli, Claudio Marchetti, Bianca Schmid, Rudi |
| description | Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (Bf) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bfabove aqueous saturation produced a similar but aborted response. Exposure to this higher Bffor 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltrans-ferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, Bf=40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation. |
| doi_str_mv | 10.1073/pnas.0308452100 |
| format | Article |
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Donald ; Pascolo, Lorella ; Tiribelli, Claudio ; Marchetti, Bianca ; Schmid, Rudi</creator><creatorcontrib>Gennuso, Florinda ; Fernetti, Cristina ; Tirolo, Cataldo ; Testa, Nuccio ; L'Episcopo, Francesca ; Caniglia, Salvo ; Morale, Maria Concetta ; Ostrow, J. Donald ; Pascolo, Lorella ; Tiribelli, Claudio ; Marchetti, Bianca ; Schmid, Rudi</creatorcontrib><description>Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (Bf) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bfabove aqueous saturation produced a similar but aborted response. Exposure to this higher Bffor 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltrans-ferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, Bf=40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0308452100</identifier><identifier>PMID: 14983033</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Animals, Newborn ; Apoptosis ; Astrocytes ; Astrocytes - cytology ; Astrocytes - drug effects ; Astrocytes - pathology ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; Bilirubin - physiology ; Bilirubin - toxicity ; Biological Sciences ; Brain - cytology ; Cell Membrane - physiology ; Cell Membrane - ultrastructure ; Cell membranes ; Cells, Cultured ; chemoprotection ; Cultured cells ; Dosage ; Drug resistance ; Fluorescent antibody techniques ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - physiology ; Golgi apparatus ; Golgi Apparatus - physiology ; Golgi Apparatus - ultrastructure ; Leukotriene Antagonists - pharmacology ; Medical research ; Mice ; Neuroglia ; Neurons ; Propionates - pharmacology ; Protein Transport ; Proteins ; Quinolines - pharmacology ; Toxicity ; Up regulation</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2004-02, Vol.101 (8), p.2470-2475</ispartof><rights>Copyright 1993/2004 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Feb 24, 2004</rights><rights>Copyright © 2004, The National Academy of Sciences 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-a10e125c13c7717d335d84cf8bd0ec7a5a0862ac26830f622a33702fcdecb1973</citedby><cites>FETCH-LOGICAL-c590t-a10e125c13c7717d335d84cf8bd0ec7a5a0862ac26830f622a33702fcdecb1973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/101/8.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3371315$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3371315$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14983033$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gennuso, Florinda</creatorcontrib><creatorcontrib>Fernetti, Cristina</creatorcontrib><creatorcontrib>Tirolo, Cataldo</creatorcontrib><creatorcontrib>Testa, Nuccio</creatorcontrib><creatorcontrib>L'Episcopo, Francesca</creatorcontrib><creatorcontrib>Caniglia, Salvo</creatorcontrib><creatorcontrib>Morale, Maria Concetta</creatorcontrib><creatorcontrib>Ostrow, J. Donald</creatorcontrib><creatorcontrib>Pascolo, Lorella</creatorcontrib><creatorcontrib>Tiribelli, Claudio</creatorcontrib><creatorcontrib>Marchetti, Bianca</creatorcontrib><creatorcontrib>Schmid, Rudi</creatorcontrib><title>Bilirubin Protects Astrocytes from Its Own Toxicity by Inducing Up-Regulation and Translocation of Multidrug Resistance-Associated Protein 1 (Mrp1)</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (Bf) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bfabove aqueous saturation produced a similar but aborted response. Exposure to this higher Bffor 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltrans-ferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, Bf=40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Apoptosis</subject><subject>Astrocytes</subject><subject>Astrocytes - cytology</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - pathology</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>Bilirubin - physiology</subject><subject>Bilirubin - toxicity</subject><subject>Biological Sciences</subject><subject>Brain - cytology</subject><subject>Cell Membrane - physiology</subject><subject>Cell Membrane - ultrastructure</subject><subject>Cell membranes</subject><subject>Cells, Cultured</subject><subject>chemoprotection</subject><subject>Cultured cells</subject><subject>Dosage</subject><subject>Drug resistance</subject><subject>Fluorescent antibody techniques</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - physiology</subject><subject>Golgi apparatus</subject><subject>Golgi Apparatus - physiology</subject><subject>Golgi Apparatus - ultrastructure</subject><subject>Leukotriene Antagonists - pharmacology</subject><subject>Medical research</subject><subject>Mice</subject><subject>Neuroglia</subject><subject>Neurons</subject><subject>Propionates - pharmacology</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>Quinolines - pharmacology</subject><subject>Toxicity</subject><subject>Up regulation</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtvEzEUhUcIRNPCmg1CFgsei2mvH_NasAgVj0itiqp0bXk8nuBoYk_9oM3v4A_jaKKmsGBl6fo7x-f6ZNkrDKcYKno2GuFPgULNCoIBnmQzDA3OS9bA02wGQKq8ZoQdZcferwGgKWp4nh1h1tQUKJ1lvz_rQbvYaoN-OBuUDB7NfXBWboPyqHd2gxZpdnVn0NLea6nDFrVbtDBdlNqs0M2YX6tVHETQ1iBhOrR0wvjBymlie3QZh6A7F1foWnntgzBS5XPvrdQiqG56OAXA6MOlG_HHF9mzXgxevdyfJ9nN1y_L8-_5xdW3xfn8IpdFAyEXGBQmhcRUVhWuOkqLrmayr9sOlKxEIaAuiZCkTLv2JSGC0gpILzslW9xU9CT7NPmOsd2oTioTnBj46PRGuC23QvO_b4z-yVf2F6dF2VQs6d_t9c7eRuUD32gv1TAIo2z0HDekZJSQBL79B1zb6EzajRPAlDWsxAk6myDprPdO9Q9BMPBd2XxXNj-UnRRvHuc_8Pt2HwE75cEO85oTVu0c3v8X4H0chqDuQyJfT-TaB-se0PSjmOKC_gGpcsk8</recordid><startdate>20040224</startdate><enddate>20040224</enddate><creator>Gennuso, Florinda</creator><creator>Fernetti, Cristina</creator><creator>Tirolo, Cataldo</creator><creator>Testa, Nuccio</creator><creator>L'Episcopo, Francesca</creator><creator>Caniglia, Salvo</creator><creator>Morale, Maria Concetta</creator><creator>Ostrow, J. Donald</creator><creator>Pascolo, Lorella</creator><creator>Tiribelli, Claudio</creator><creator>Marchetti, Bianca</creator><creator>Schmid, Rudi</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7U7</scope><scope>5PM</scope></search><sort><creationdate>20040224</creationdate><title>Bilirubin Protects Astrocytes from Its Own Toxicity by Inducing Up-Regulation and Translocation of Multidrug Resistance-Associated Protein 1 (Mrp1)</title><author>Gennuso, Florinda ; Fernetti, Cristina ; Tirolo, Cataldo ; Testa, Nuccio ; L'Episcopo, Francesca ; Caniglia, Salvo ; Morale, Maria Concetta ; Ostrow, J. 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Donald</au><au>Pascolo, Lorella</au><au>Tiribelli, Claudio</au><au>Marchetti, Bianca</au><au>Schmid, Rudi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bilirubin Protects Astrocytes from Its Own Toxicity by Inducing Up-Regulation and Translocation of Multidrug Resistance-Associated Protein 1 (Mrp1)</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2004-02-24</date><risdate>2004</risdate><volume>101</volume><issue>8</issue><spage>2470</spage><epage>2475</epage><pages>2470-2475</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (Bf) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bfabove aqueous saturation produced a similar but aborted response. Exposure to this higher Bffor 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltrans-ferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, Bf=40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>14983033</pmid><doi>10.1073/pnas.0308452100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2004-02, Vol.101 (8), p.2470-2475 |
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| subjects | Animals Animals, Newborn Apoptosis Astrocytes Astrocytes - cytology Astrocytes - drug effects Astrocytes - pathology ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism Bilirubin - physiology Bilirubin - toxicity Biological Sciences Brain - cytology Cell Membrane - physiology Cell Membrane - ultrastructure Cell membranes Cells, Cultured chemoprotection Cultured cells Dosage Drug resistance Fluorescent antibody techniques Gene Expression Regulation - drug effects Gene Expression Regulation - physiology Golgi apparatus Golgi Apparatus - physiology Golgi Apparatus - ultrastructure Leukotriene Antagonists - pharmacology Medical research Mice Neuroglia Neurons Propionates - pharmacology Protein Transport Proteins Quinolines - pharmacology Toxicity Up regulation |
| title | Bilirubin Protects Astrocytes from Its Own Toxicity by Inducing Up-Regulation and Translocation of Multidrug Resistance-Associated Protein 1 (Mrp1) |
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