The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin
Hepatotoxicity caused by the mushroom poison alpha-amanitin is an unusual but serious cause of death and liver transplantation. Understanding the mechanisms of alpha-amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporte...
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| Veröffentlicht in: | Archives of toxicology 2004-02, Vol.78 (2), p.68-73 |
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| creator | GUNDALA, Sri WELLS, Lisa D MILLIANO, Michael T TALKAD, Vanita LUXON, Bruce A NEUSCHWANDER-TETRI, Brent A |
| description | Hepatotoxicity caused by the mushroom poison alpha-amanitin is an unusual but serious cause of death and liver transplantation. Understanding the mechanisms of alpha-amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporter is responsible for alpha-amanitin uptake, we tested the hypothesis that Na(+)-taurocholate cotransporter polypeptide (Ntcp) facilitates hepatocellular alpha-amanitin uptake. Human hepatoblastoma cells (HepG2), cells that have lost native Ntcp expression, were stably transfected with the rat Ntcp gene. Taurocholate uptake by the transfected cells exhibited a physiologically normal K(m) and V(max). A toxicologically relevant functional assay for alpha-amanitin uptake was developed by measuring its ability to block cytokine-induced synthesis of interleukin-1 receptor antagonist (IL-1Ra) mRNA. Treatment with interleukin-1beta (10 ng/ml) and interleukin-6 (100 ng/ml) increased IL-1Ra mRNA abundance 8.6-fold and 15.6-fold in HepG2 cells and Ntcp-transfected cells, respectively. Pretreatment of transfected cells with 1 micro M alpha-amanitin for 6-10 h almost completely blocked induction of IL-1Ra mRNA (1.9-fold induction) whereas pretreatment of non-transfected cells did not block induction of IL-1Ra mRNA (21.6-fold induction, P |
| doi_str_mv | 10.1007/s00204-003-0527-y |
| format | Article |
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Understanding the mechanisms of alpha-amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporter is responsible for alpha-amanitin uptake, we tested the hypothesis that Na(+)-taurocholate cotransporter polypeptide (Ntcp) facilitates hepatocellular alpha-amanitin uptake. Human hepatoblastoma cells (HepG2), cells that have lost native Ntcp expression, were stably transfected with the rat Ntcp gene. Taurocholate uptake by the transfected cells exhibited a physiologically normal K(m) and V(max). A toxicologically relevant functional assay for alpha-amanitin uptake was developed by measuring its ability to block cytokine-induced synthesis of interleukin-1 receptor antagonist (IL-1Ra) mRNA. Treatment with interleukin-1beta (10 ng/ml) and interleukin-6 (100 ng/ml) increased IL-1Ra mRNA abundance 8.6-fold and 15.6-fold in HepG2 cells and Ntcp-transfected cells, respectively. Pretreatment of transfected cells with 1 micro M alpha-amanitin for 6-10 h almost completely blocked induction of IL-1Ra mRNA (1.9-fold induction) whereas pretreatment of non-transfected cells did not block induction of IL-1Ra mRNA (21.6-fold induction, P<0.02 compared with stimulated transfected cells without alpha-amanitin). These findings demonstrate that Ntcp may be an important mediator of alpha-amanitin uptake by the liver.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-003-0527-y</identifier><identifier>PMID: 14598021</identifier><identifier>CODEN: ARTODN</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Amanitins - pharmacokinetics ; Amanitins - pharmacology ; Animals ; Biological and medical sciences ; Drug Combinations ; Enzyme Inhibitors - pharmacokinetics ; Hepatoblastoma - drug therapy ; Hepatoblastoma - pathology ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1 - pharmacology ; Interleukin-6 - pharmacology ; Medical sciences ; Nucleic Acid Synthesis Inhibitors - pharmacokinetics ; Organic Anion Transporters, Sodium-Dependent - metabolism ; Organic Anion Transporters, Sodium-Dependent - pharmacology ; Rats ; RNA, Messenger - antagonists & inhibitors ; RNA, Messenger - biosynthesis ; RNA, Messenger - drug effects ; Sialoglycoproteins - biosynthesis ; Sialoglycoproteins - genetics ; Symporters - metabolism ; Symporters - pharmacology ; Toxicology ; Transfection ; Tumor Cells, Cultured</subject><ispartof>Archives of toxicology, 2004-02, Vol.78 (2), p.68-73</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15939191$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14598021$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GUNDALA, Sri</creatorcontrib><creatorcontrib>WELLS, Lisa D</creatorcontrib><creatorcontrib>MILLIANO, Michael T</creatorcontrib><creatorcontrib>TALKAD, Vanita</creatorcontrib><creatorcontrib>LUXON, Bruce A</creatorcontrib><creatorcontrib>NEUSCHWANDER-TETRI, Brent A</creatorcontrib><title>The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><description>Hepatotoxicity caused by the mushroom poison alpha-amanitin is an unusual but serious cause of death and liver transplantation. Understanding the mechanisms of alpha-amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporter is responsible for alpha-amanitin uptake, we tested the hypothesis that Na(+)-taurocholate cotransporter polypeptide (Ntcp) facilitates hepatocellular alpha-amanitin uptake. Human hepatoblastoma cells (HepG2), cells that have lost native Ntcp expression, were stably transfected with the rat Ntcp gene. Taurocholate uptake by the transfected cells exhibited a physiologically normal K(m) and V(max). A toxicologically relevant functional assay for alpha-amanitin uptake was developed by measuring its ability to block cytokine-induced synthesis of interleukin-1 receptor antagonist (IL-1Ra) mRNA. Treatment with interleukin-1beta (10 ng/ml) and interleukin-6 (100 ng/ml) increased IL-1Ra mRNA abundance 8.6-fold and 15.6-fold in HepG2 cells and Ntcp-transfected cells, respectively. Pretreatment of transfected cells with 1 micro M alpha-amanitin for 6-10 h almost completely blocked induction of IL-1Ra mRNA (1.9-fold induction) whereas pretreatment of non-transfected cells did not block induction of IL-1Ra mRNA (21.6-fold induction, P<0.02 compared with stimulated transfected cells without alpha-amanitin). These findings demonstrate that Ntcp may be an important mediator of alpha-amanitin uptake by the liver.</description><subject>Amanitins - pharmacokinetics</subject><subject>Amanitins - pharmacology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Drug Combinations</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Hepatoblastoma - drug therapy</subject><subject>Hepatoblastoma - pathology</subject><subject>Interleukin 1 Receptor Antagonist Protein</subject><subject>Interleukin-1 - pharmacology</subject><subject>Interleukin-6 - pharmacology</subject><subject>Medical sciences</subject><subject>Nucleic Acid Synthesis Inhibitors - pharmacokinetics</subject><subject>Organic Anion Transporters, Sodium-Dependent - metabolism</subject><subject>Organic Anion Transporters, Sodium-Dependent - pharmacology</subject><subject>Rats</subject><subject>RNA, Messenger - antagonists & inhibitors</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - drug effects</subject><subject>Sialoglycoproteins - biosynthesis</subject><subject>Sialoglycoproteins - genetics</subject><subject>Symporters - metabolism</subject><subject>Symporters - pharmacology</subject><subject>Toxicology</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><issn>0340-5761</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0EtKxEAQBuBGFGccPYAb6Y3uWqsfmU6WIr5g0M24DpWkwrR2HqY74BzLi3gmI464Kig-fqp-xk4lXEoAexUAFBgBoAUkyortHptLo5UAq9N9NgdtQCR2KWfsKIRXAKnSTB-ymTRJloKSc-bWG-Ib6jF2JXk_ehx44TxxLF3F44Bt6Lsh0sCfYtnzelp7FzFS4GMf8Y14V_M4ZXiKG_S8GcNm6LqGx-7DtfzrU2CDrYuuPWYHNfpAJ7u5YC93t-ubB7F6vn-8uV6JXi3TKMiaUi9TW-g6IUhIydSQzqxJq1qZooKlQUwybcFaSVgQ2crYNCnqwuqqrvSCXfzm9kP3PlKIeePCz2_YUjeGXNpMTd5O8GwHx6KhKu8H1-Cwzf_KmcD5DmAo0ddTGaUL_266IpOZ1N-USXZV</recordid><startdate>20040201</startdate><enddate>20040201</enddate><creator>GUNDALA, Sri</creator><creator>WELLS, Lisa D</creator><creator>MILLIANO, Michael T</creator><creator>TALKAD, Vanita</creator><creator>LUXON, Bruce A</creator><creator>NEUSCHWANDER-TETRI, Brent A</creator><general>Springer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20040201</creationdate><title>The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin</title><author>GUNDALA, Sri ; WELLS, Lisa D ; MILLIANO, Michael T ; TALKAD, Vanita ; LUXON, Bruce A ; NEUSCHWANDER-TETRI, Brent A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p268t-e74c3687b3f5e05e2184e39748df24bd064aa59370771eabee7d4785bfb73dfd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Amanitins - pharmacokinetics</topic><topic>Amanitins - pharmacology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Drug Combinations</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Hepatoblastoma - drug therapy</topic><topic>Hepatoblastoma - pathology</topic><topic>Interleukin 1 Receptor Antagonist Protein</topic><topic>Interleukin-1 - pharmacology</topic><topic>Interleukin-6 - pharmacology</topic><topic>Medical sciences</topic><topic>Nucleic Acid Synthesis Inhibitors - pharmacokinetics</topic><topic>Organic Anion Transporters, Sodium-Dependent - metabolism</topic><topic>Organic Anion Transporters, Sodium-Dependent - pharmacology</topic><topic>Rats</topic><topic>RNA, Messenger - antagonists & inhibitors</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - drug effects</topic><topic>Sialoglycoproteins - biosynthesis</topic><topic>Sialoglycoproteins - genetics</topic><topic>Symporters - metabolism</topic><topic>Symporters - pharmacology</topic><topic>Toxicology</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GUNDALA, Sri</creatorcontrib><creatorcontrib>WELLS, Lisa D</creatorcontrib><creatorcontrib>MILLIANO, Michael T</creatorcontrib><creatorcontrib>TALKAD, Vanita</creatorcontrib><creatorcontrib>LUXON, Bruce A</creatorcontrib><creatorcontrib>NEUSCHWANDER-TETRI, Brent A</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Archives of toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GUNDALA, Sri</au><au>WELLS, Lisa D</au><au>MILLIANO, Michael T</au><au>TALKAD, Vanita</au><au>LUXON, Bruce A</au><au>NEUSCHWANDER-TETRI, Brent A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin</atitle><jtitle>Archives of toxicology</jtitle><addtitle>Arch Toxicol</addtitle><date>2004-02-01</date><risdate>2004</risdate><volume>78</volume><issue>2</issue><spage>68</spage><epage>73</epage><pages>68-73</pages><issn>0340-5761</issn><eissn>1432-0738</eissn><coden>ARTODN</coden><abstract>Hepatotoxicity caused by the mushroom poison alpha-amanitin is an unusual but serious cause of death and liver transplantation. Understanding the mechanisms of alpha-amanitin uptake may lead to rational therapeutic approaches. Because older data suggested that a sodium-dependent bile acid transporter is responsible for alpha-amanitin uptake, we tested the hypothesis that Na(+)-taurocholate cotransporter polypeptide (Ntcp) facilitates hepatocellular alpha-amanitin uptake. Human hepatoblastoma cells (HepG2), cells that have lost native Ntcp expression, were stably transfected with the rat Ntcp gene. Taurocholate uptake by the transfected cells exhibited a physiologically normal K(m) and V(max). A toxicologically relevant functional assay for alpha-amanitin uptake was developed by measuring its ability to block cytokine-induced synthesis of interleukin-1 receptor antagonist (IL-1Ra) mRNA. Treatment with interleukin-1beta (10 ng/ml) and interleukin-6 (100 ng/ml) increased IL-1Ra mRNA abundance 8.6-fold and 15.6-fold in HepG2 cells and Ntcp-transfected cells, respectively. Pretreatment of transfected cells with 1 micro M alpha-amanitin for 6-10 h almost completely blocked induction of IL-1Ra mRNA (1.9-fold induction) whereas pretreatment of non-transfected cells did not block induction of IL-1Ra mRNA (21.6-fold induction, P<0.02 compared with stimulated transfected cells without alpha-amanitin). These findings demonstrate that Ntcp may be an important mediator of alpha-amanitin uptake by the liver.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>14598021</pmid><doi>10.1007/s00204-003-0527-y</doi><tpages>6</tpages></addata></record> |
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| subjects | Amanitins - pharmacokinetics Amanitins - pharmacology Animals Biological and medical sciences Drug Combinations Enzyme Inhibitors - pharmacokinetics Hepatoblastoma - drug therapy Hepatoblastoma - pathology Interleukin 1 Receptor Antagonist Protein Interleukin-1 - pharmacology Interleukin-6 - pharmacology Medical sciences Nucleic Acid Synthesis Inhibitors - pharmacokinetics Organic Anion Transporters, Sodium-Dependent - metabolism Organic Anion Transporters, Sodium-Dependent - pharmacology Rats RNA, Messenger - antagonists & inhibitors RNA, Messenger - biosynthesis RNA, Messenger - drug effects Sialoglycoproteins - biosynthesis Sialoglycoproteins - genetics Symporters - metabolism Symporters - pharmacology Toxicology Transfection Tumor Cells, Cultured |
| title | The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin α-amanitin |
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