Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor
Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of...
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| Veröffentlicht in: | European journal of pharmacology 2002-08, Vol.450 (2), p.115-121 |
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| creator | van Giersbergen, Paul L.M Gnerre, Carmela Treiber, Alexander Dingemanse, Jasper Meyer, Urs A |
| description | Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome
P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC
50 of 19.9 μM, whereas rifampicin had an EC
50 value of 1.9 μM. Ro 47-8634 (4-
tert-butyl-
N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2′-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs. |
| doi_str_mv | 10.1016/S0014-2999(02)02075-7 |
| format | Article |
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P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC
50 of 19.9 μM, whereas rifampicin had an EC
50 value of 1.9 μM. Ro 47-8634 (4-
tert-butyl-
N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2′-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/S0014-2999(02)02075-7</identifier><identifier>PMID: 12206849</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Animals ; Biological and medical sciences ; Bosentan ; Cell Line ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome P450 enzyme induction ; Dose-Response Relationship, Drug ; Endothelin Receptor Antagonists ; General pharmacology ; Glibenclamide ; Glyburide - pharmacology ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Humans ; Hypoglycemic Agents - pharmacology ; Medical sciences ; Mice ; Miscellaneous ; Pharmacology. Drug treatments ; Pregnane X Receptor ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Steroid - agonists ; Sulfonamides - metabolism ; Sulfonamides - pharmacology</subject><ispartof>European journal of pharmacology, 2002-08, Vol.450 (2), p.115-121</ispartof><rights>2002 Elsevier Science B.V.</rights><rights>2002 INIST-CNRS</rights><rights>Copyright 2002 Elsevier Science B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-d298d748deb52c476cd60a567fdb17159e7db6aba1016d440239ef4012e94dc83</citedby><cites>FETCH-LOGICAL-c509t-d298d748deb52c476cd60a567fdb17159e7db6aba1016d440239ef4012e94dc83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0014-2999(02)02075-7$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13859059$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12206849$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Giersbergen, Paul L.M</creatorcontrib><creatorcontrib>Gnerre, Carmela</creatorcontrib><creatorcontrib>Treiber, Alexander</creatorcontrib><creatorcontrib>Dingemanse, Jasper</creatorcontrib><creatorcontrib>Meyer, Urs A</creatorcontrib><title>Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome
P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC
50 of 19.9 μM, whereas rifampicin had an EC
50 value of 1.9 μM. Ro 47-8634 (4-
tert-butyl-
N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2′-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bosentan</subject><subject>Cell Line</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome P450 enzyme induction</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endothelin Receptor Antagonists</subject><subject>General pharmacology</subject><subject>Glibenclamide</subject><subject>Glyburide - pharmacology</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Humans</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Miscellaneous</subject><subject>Pharmacology. Drug treatments</subject><subject>Pregnane X Receptor</subject><subject>Receptors, Cytoplasmic and Nuclear - agonists</subject><subject>Receptors, Steroid - agonists</subject><subject>Sulfonamides - metabolism</subject><subject>Sulfonamides - pharmacology</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0M9vFCEUwHHSaNrtjz-hhouNJk59sDAMJ1MbtU2aeFCTphfCwJuKmWVWYJr435ftbtqjJy6f94AvIacMzhmw9uMPACYarrV-B_w9cFCyUXtkwTqlG1CMvyKLZ3JADnP-AwBSc7lPDhjn0HZCL8jd5yljLDZ-oJb62Y4Uo5_KbxxDpAkdrsuUqK3ifoohl8pcCQ-2YKZV0XXC-2gj0lsaZzeiTc9Tx-T1YMeMJ7vziPz6-uXn5VVz8_3b9eXFTeMk6NJ4rjuvROexl9wJ1TrfgpWtGnzPFJMale9b29vNt70QwJcaBwGMoxbedcsjcrbdu07T3xlzMauQHY5jfdY0Z6M4iLbroEK5hS5NOScczDqFlU3_DAOz2W6eoppNMQPcPEU1qs692V0w9yv0L1O7ihW83QGbnR2HZKML-cUtO6lr-uo-bR3WHA8Bk8kuYHToQ41WjJ_Cf57yCCUEk-8</recordid><startdate>20020823</startdate><enddate>20020823</enddate><creator>van Giersbergen, Paul L.M</creator><creator>Gnerre, Carmela</creator><creator>Treiber, Alexander</creator><creator>Dingemanse, Jasper</creator><creator>Meyer, Urs A</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20020823</creationdate><title>Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor</title><author>van Giersbergen, Paul L.M ; Gnerre, Carmela ; Treiber, Alexander ; Dingemanse, Jasper ; Meyer, Urs A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-d298d748deb52c476cd60a567fdb17159e7db6aba1016d440239ef4012e94dc83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bosentan</topic><topic>Cell Line</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Cytochrome P450 enzyme induction</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endothelin Receptor Antagonists</topic><topic>General pharmacology</topic><topic>Glibenclamide</topic><topic>Glyburide - pharmacology</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Humans</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Pharmacology. Drug treatments</topic><topic>Pregnane X Receptor</topic><topic>Receptors, Cytoplasmic and Nuclear - agonists</topic><topic>Receptors, Steroid - agonists</topic><topic>Sulfonamides - metabolism</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Giersbergen, Paul L.M</creatorcontrib><creatorcontrib>Gnerre, Carmela</creatorcontrib><creatorcontrib>Treiber, Alexander</creatorcontrib><creatorcontrib>Dingemanse, Jasper</creatorcontrib><creatorcontrib>Meyer, Urs 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>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Giersbergen, Paul L.M</au><au>Gnerre, Carmela</au><au>Treiber, Alexander</au><au>Dingemanse, Jasper</au><au>Meyer, Urs A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2002-08-23</date><risdate>2002</risdate><volume>450</volume><issue>2</issue><spage>115</spage><epage>121</epage><pages>115-121</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome
P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC
50 of 19.9 μM, whereas rifampicin had an EC
50 value of 1.9 μM. Ro 47-8634 (4-
tert-butyl-
N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2′-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>12206849</pmid><doi>10.1016/S0014-2999(02)02075-7</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Bosentan Cell Line Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 enzyme induction Dose-Response Relationship, Drug Endothelin Receptor Antagonists General pharmacology Glibenclamide Glyburide - pharmacology Hepatocytes - drug effects Hepatocytes - enzymology Humans Hypoglycemic Agents - pharmacology Medical sciences Mice Miscellaneous Pharmacology. Drug treatments Pregnane X Receptor Receptors, Cytoplasmic and Nuclear - agonists Receptors, Steroid - agonists Sulfonamides - metabolism Sulfonamides - pharmacology |
| title | Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor |
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