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Rifampicin Is Not an Activator of Glucocorticoid Receptor
Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients. Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is evidence that increased levels of glucocorticoids ma...
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Published in: | Molecular pharmacology 2000-04, Vol.57 (4), p.732-737 |
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creator | Herr, A S Wochnik, G M Rosenhagen, M C Holsboer, F Rein, T |
description | Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients.
Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is
evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the
side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to
determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal
HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone
led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used
to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to
GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil
or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our
results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of
rifampicin treatment are a consequence of GR activation. |
doi_str_mv | 10.1124/mol.57.4.732 |
format | article |
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Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is
evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the
side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to
determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal
HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone
led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used
to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to
GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil
or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our
results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of
rifampicin treatment are a consequence of GR activation.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.57.4.732</identifier><identifier>PMID: 10727519</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Animals ; Antibiotics, Antitubercular - pharmacology ; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors ; Cells, Cultured ; Dexamethasone - pharmacology ; Drug Interactions ; Hippocampus - cytology ; Hippocampus - drug effects ; Humans ; Hydrocortisone - pharmacology ; Ligands ; Mice ; Neurons - drug effects ; Neurons - metabolism ; Promoter Regions, Genetic ; Receptors, Glucocorticoid - agonists ; Receptors, Glucocorticoid - metabolism ; Rifampin - pharmacology ; Transcription, Genetic - drug effects</subject><ispartof>Molecular pharmacology, 2000-04, Vol.57 (4), p.732-737</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c317t-296bf8381f6f6a071476437a89985e6f06955ae2f6503cf5952e9235373bae803</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10727519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herr, A S</creatorcontrib><creatorcontrib>Wochnik, G M</creatorcontrib><creatorcontrib>Rosenhagen, M C</creatorcontrib><creatorcontrib>Holsboer, F</creatorcontrib><creatorcontrib>Rein, T</creatorcontrib><title>Rifampicin Is Not an Activator of Glucocorticoid Receptor</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients.
Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is
evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the
side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to
determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal
HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone
led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used
to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to
GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil
or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our
results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of
rifampicin treatment are a consequence of GR activation.</description><subject>Animals</subject><subject>Antibiotics, Antitubercular - pharmacology</subject><subject>ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors</subject><subject>Cells, Cultured</subject><subject>Dexamethasone - pharmacology</subject><subject>Drug Interactions</subject><subject>Hippocampus - cytology</subject><subject>Hippocampus - drug effects</subject><subject>Humans</subject><subject>Hydrocortisone - pharmacology</subject><subject>Ligands</subject><subject>Mice</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, Glucocorticoid - agonists</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Rifampin - pharmacology</subject><subject>Transcription, Genetic - drug effects</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><recordid>eNpNkM9LwzAcxYMobk5vnqUXb7bmmzS_jmPoHAyFoeAtZFmyRdqlpJ2y_95KBT29w_vw4H0QugZcAJDyvo5VwURRFoKSEzQGRiDHAHCKxhgTnkvF3kfoom0_MIaSSXyORoAFEQzUGKlV8KZugg37bNFmz7HLzD6b2i58mi6mLPpsXh1stDF1wcawyVbOuqavLtGZN1Xrrn5zgt4eH15nT_nyZb6YTZe5pSC6nCi-9pJK8NxzgwWUgpdUGKmUZI57zBVjxhHPGabWM8WIU4QyKujaOInpBN0NuzbFtk3O6yaF2qSjBqx_DOjegGZCl7o30OM3A94c1rXb_IOHyz1wOwC7sN19heR0szOpNjZWcXv8G_oGz1BiWw</recordid><startdate>20000401</startdate><enddate>20000401</enddate><creator>Herr, A S</creator><creator>Wochnik, G M</creator><creator>Rosenhagen, M C</creator><creator>Holsboer, F</creator><creator>Rein, T</creator><general>American Society for Pharmacology and Experimental Therapeutics</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></search><sort><creationdate>20000401</creationdate><title>Rifampicin Is Not an Activator of Glucocorticoid Receptor</title><author>Herr, A S ; Wochnik, G M ; Rosenhagen, M C ; Holsboer, F ; Rein, T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c317t-296bf8381f6f6a071476437a89985e6f06955ae2f6503cf5952e9235373bae803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>Antibiotics, Antitubercular - pharmacology</topic><topic>ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors</topic><topic>Cells, Cultured</topic><topic>Dexamethasone - pharmacology</topic><topic>Drug Interactions</topic><topic>Hippocampus - cytology</topic><topic>Hippocampus - drug effects</topic><topic>Humans</topic><topic>Hydrocortisone - pharmacology</topic><topic>Ligands</topic><topic>Mice</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>Receptors, Glucocorticoid - agonists</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Rifampin - pharmacology</topic><topic>Transcription, Genetic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herr, A S</creatorcontrib><creatorcontrib>Wochnik, G M</creatorcontrib><creatorcontrib>Rosenhagen, M C</creatorcontrib><creatorcontrib>Holsboer, F</creatorcontrib><creatorcontrib>Rein, T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Herr, A S</au><au>Wochnik, G M</au><au>Rosenhagen, M C</au><au>Holsboer, F</au><au>Rein, T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rifampicin Is Not an Activator of Glucocorticoid Receptor</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>2000-04-01</date><risdate>2000</risdate><volume>57</volume><issue>4</issue><spage>732</spage><epage>737</epage><pages>732-737</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients.
Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is
evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the
side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to
determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal
HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone
led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used
to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to
GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil
or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our
results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of
rifampicin treatment are a consequence of GR activation.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>10727519</pmid><doi>10.1124/mol.57.4.732</doi><tpages>6</tpages></addata></record> |
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source | Free Full-Text Journals in Chemistry |
subjects | Animals Antibiotics, Antitubercular - pharmacology ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors Cells, Cultured Dexamethasone - pharmacology Drug Interactions Hippocampus - cytology Hippocampus - drug effects Humans Hydrocortisone - pharmacology Ligands Mice Neurons - drug effects Neurons - metabolism Promoter Regions, Genetic Receptors, Glucocorticoid - agonists Receptors, Glucocorticoid - metabolism Rifampin - pharmacology Transcription, Genetic - drug effects |
title | Rifampicin Is Not an Activator of Glucocorticoid Receptor |
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