Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles
Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be app...
Gespeichert in:
Veröffentlicht in: | Toxicology and applied pharmacology 2001-08, Vol.175 (1), p.28-42 |
---|---|
Hauptverfasser: | , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 42 |
---|---|
container_issue | 1 |
container_start_page | 28 |
container_title | Toxicology and applied pharmacology |
container_volume | 175 |
creator | Waring, Jeffrey F. Jolly, Robert A. Ciurlionis, Rita Lum, Pek Yee Praestgaard, Jens T. Morfitt, David C. Buratto, Bruno Roberts, Chris Schadt, Eric Ulrich, Roger G. |
description | Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins. |
doi_str_mv | 10.1006/taap.2001.9243 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_17912666</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0041008X01992439</els_id><sourcerecordid>17912666</sourcerecordid><originalsourceid>FETCH-LOGICAL-c493t-b7fc02d7da17ab2d0ab8a7c320f4980263f5cdc237994d8a956b1167bcadffcc3</originalsourceid><addsrcrecordid>eNp1kEFv1DAQRi0EotuWK0eUA-KW7djOJvERVqVFakUPrdSbNbHHYJSNgyeL2n9Pol2JXjjNYd73zegJ8V7CWgLUFxPiuFYAcm1UpV-JlQRTl6C1fi1WAJUsAdrHE3HK_AsATFXJt-JEyg0YUNVKPG77PU-U4_CjSKG4phGnNKWnOHDxBZl8kYbiltxPHCLvFuR-Xro4PRcPvISuaKDi8mnMxBxn9i6nEHvic_EmYM_07jjPxMPXy_vtdXnz_erb9vNN6Sqjp7JrggPlG4-ywU55wK7FxmkFoTItqFqHjfNO6caYyrdoNnUnZd10Dn0Izukz8enQO-b0e0882V1kR32PA6U9W9kYqeq6nsH1AXQ5MWcKdsxxh_nZSrCLS7u4tItLu7icAx-OzftuR_4ffpQ3Ax-PALLDPmQcXOQXtUa2zXK4PWA0a_gTKVt2kQZHPmZyk_Up_u-FvzmokNU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17912666</pqid></control><display><type>article</type><title>Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Waring, Jeffrey F. ; Jolly, Robert A. ; Ciurlionis, Rita ; Lum, Pek Yee ; Praestgaard, Jens T. ; Morfitt, David C. ; Buratto, Bruno ; Roberts, Chris ; Schadt, Eric ; Ulrich, Roger G.</creator><creatorcontrib>Waring, Jeffrey F. ; Jolly, Robert A. ; Ciurlionis, Rita ; Lum, Pek Yee ; Praestgaard, Jens T. ; Morfitt, David C. ; Buratto, Bruno ; Roberts, Chris ; Schadt, Eric ; Ulrich, Roger G.</creatorcontrib><description>Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1006/taap.2001.9243</identifier><identifier>PMID: 11509024</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>San Diego, CA: Elsevier Inc</publisher><subject>Amiodarone - toxicity ; Animals ; Biological and medical sciences ; Carbon Tetrachloride - toxicity ; Chlorodiphenyl (54% Chlorine) - toxicity ; cluster ; Diethylnitrosamine - toxicity ; diquat ; Gene Expression - drug effects ; Gene Expression Profiling - methods ; General aspects. Methods ; hepatotoxicity ; Liver - drug effects ; Liver - pathology ; Liver - physiology ; Male ; Medical sciences ; microarray ; necrosis ; Phylogeny ; profile ; Propanols - toxicity ; Rats ; Rats, Sprague-Dawley ; Toxicology ; Toxins, Biological - classification ; Toxins, Biological - toxicity</subject><ispartof>Toxicology and applied pharmacology, 2001-08, Vol.175 (1), p.28-42</ispartof><rights>2001 Academic Press</rights><rights>2001 INIST-CNRS</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-b7fc02d7da17ab2d0ab8a7c320f4980263f5cdc237994d8a956b1167bcadffcc3</citedby><cites>FETCH-LOGICAL-c493t-b7fc02d7da17ab2d0ab8a7c320f4980263f5cdc237994d8a956b1167bcadffcc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0041008X01992439$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1091876$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11509024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Waring, Jeffrey F.</creatorcontrib><creatorcontrib>Jolly, Robert A.</creatorcontrib><creatorcontrib>Ciurlionis, Rita</creatorcontrib><creatorcontrib>Lum, Pek Yee</creatorcontrib><creatorcontrib>Praestgaard, Jens T.</creatorcontrib><creatorcontrib>Morfitt, David C.</creatorcontrib><creatorcontrib>Buratto, Bruno</creatorcontrib><creatorcontrib>Roberts, Chris</creatorcontrib><creatorcontrib>Schadt, Eric</creatorcontrib><creatorcontrib>Ulrich, Roger G.</creatorcontrib><title>Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins.</description><subject>Amiodarone - toxicity</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Carbon Tetrachloride - toxicity</subject><subject>Chlorodiphenyl (54% Chlorine) - toxicity</subject><subject>cluster</subject><subject>Diethylnitrosamine - toxicity</subject><subject>diquat</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Profiling - methods</subject><subject>General aspects. Methods</subject><subject>hepatotoxicity</subject><subject>Liver - drug effects</subject><subject>Liver - pathology</subject><subject>Liver - physiology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>microarray</subject><subject>necrosis</subject><subject>Phylogeny</subject><subject>profile</subject><subject>Propanols - toxicity</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Toxicology</subject><subject>Toxins, Biological - classification</subject><subject>Toxins, Biological - toxicity</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEFv1DAQRi0EotuWK0eUA-KW7djOJvERVqVFakUPrdSbNbHHYJSNgyeL2n9Pol2JXjjNYd73zegJ8V7CWgLUFxPiuFYAcm1UpV-JlQRTl6C1fi1WAJUsAdrHE3HK_AsATFXJt-JEyg0YUNVKPG77PU-U4_CjSKG4phGnNKWnOHDxBZl8kYbiltxPHCLvFuR-Xro4PRcPvISuaKDi8mnMxBxn9i6nEHvic_EmYM_07jjPxMPXy_vtdXnz_erb9vNN6Sqjp7JrggPlG4-ywU55wK7FxmkFoTItqFqHjfNO6caYyrdoNnUnZd10Dn0Izukz8enQO-b0e0882V1kR32PA6U9W9kYqeq6nsH1AXQ5MWcKdsxxh_nZSrCLS7u4tItLu7icAx-OzftuR_4ffpQ3Ax-PALLDPmQcXOQXtUa2zXK4PWA0a_gTKVt2kQZHPmZyk_Up_u-FvzmokNU</recordid><startdate>20010815</startdate><enddate>20010815</enddate><creator>Waring, Jeffrey F.</creator><creator>Jolly, Robert A.</creator><creator>Ciurlionis, Rita</creator><creator>Lum, Pek Yee</creator><creator>Praestgaard, Jens T.</creator><creator>Morfitt, David C.</creator><creator>Buratto, Bruno</creator><creator>Roberts, Chris</creator><creator>Schadt, Eric</creator><creator>Ulrich, Roger G.</creator><general>Elsevier Inc</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>7U7</scope><scope>C1K</scope></search><sort><creationdate>20010815</creationdate><title>Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles</title><author>Waring, Jeffrey F. ; Jolly, Robert A. ; Ciurlionis, Rita ; Lum, Pek Yee ; Praestgaard, Jens T. ; Morfitt, David C. ; Buratto, Bruno ; Roberts, Chris ; Schadt, Eric ; Ulrich, Roger G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-b7fc02d7da17ab2d0ab8a7c320f4980263f5cdc237994d8a956b1167bcadffcc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amiodarone - toxicity</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Carbon Tetrachloride - toxicity</topic><topic>Chlorodiphenyl (54% Chlorine) - toxicity</topic><topic>cluster</topic><topic>Diethylnitrosamine - toxicity</topic><topic>diquat</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression Profiling - methods</topic><topic>General aspects. Methods</topic><topic>hepatotoxicity</topic><topic>Liver - drug effects</topic><topic>Liver - pathology</topic><topic>Liver - physiology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>microarray</topic><topic>necrosis</topic><topic>Phylogeny</topic><topic>profile</topic><topic>Propanols - toxicity</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Toxicology</topic><topic>Toxins, Biological - classification</topic><topic>Toxins, Biological - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Waring, Jeffrey F.</creatorcontrib><creatorcontrib>Jolly, Robert A.</creatorcontrib><creatorcontrib>Ciurlionis, Rita</creatorcontrib><creatorcontrib>Lum, Pek Yee</creatorcontrib><creatorcontrib>Praestgaard, Jens T.</creatorcontrib><creatorcontrib>Morfitt, David C.</creatorcontrib><creatorcontrib>Buratto, Bruno</creatorcontrib><creatorcontrib>Roberts, Chris</creatorcontrib><creatorcontrib>Schadt, Eric</creatorcontrib><creatorcontrib>Ulrich, Roger G.</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Waring, Jeffrey F.</au><au>Jolly, Robert A.</au><au>Ciurlionis, Rita</au><au>Lum, Pek Yee</au><au>Praestgaard, Jens T.</au><au>Morfitt, David C.</au><au>Buratto, Bruno</au><au>Roberts, Chris</au><au>Schadt, Eric</au><au>Ulrich, Roger G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2001-08-15</date><risdate>2001</risdate><volume>175</volume><issue>1</issue><spage>28</spage><epage>42</epage><pages>28-42</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>11509024</pmid><doi>10.1006/taap.2001.9243</doi><tpages>15</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0041-008X |
ispartof | Toxicology and applied pharmacology, 2001-08, Vol.175 (1), p.28-42 |
issn | 0041-008X 1096-0333 |
language | eng |
recordid | cdi_proquest_miscellaneous_17912666 |
source | MEDLINE; Elsevier ScienceDirect Journals Complete |
subjects | Amiodarone - toxicity Animals Biological and medical sciences Carbon Tetrachloride - toxicity Chlorodiphenyl (54% Chlorine) - toxicity cluster Diethylnitrosamine - toxicity diquat Gene Expression - drug effects Gene Expression Profiling - methods General aspects. Methods hepatotoxicity Liver - drug effects Liver - pathology Liver - physiology Male Medical sciences microarray necrosis Phylogeny profile Propanols - toxicity Rats Rats, Sprague-Dawley Toxicology Toxins, Biological - classification Toxins, Biological - toxicity |
title | Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T18%3A43%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clustering%20of%20Hepatotoxins%20Based%20on%20Mechanism%20of%20Toxicity%20Using%20Gene%20Expression%20Profiles&rft.jtitle=Toxicology%20and%20applied%20pharmacology&rft.au=Waring,%20Jeffrey%20F.&rft.date=2001-08-15&rft.volume=175&rft.issue=1&rft.spage=28&rft.epage=42&rft.pages=28-42&rft.issn=0041-008X&rft.eissn=1096-0333&rft.coden=TXAPA9&rft_id=info:doi/10.1006/taap.2001.9243&rft_dat=%3Cproquest_cross%3E17912666%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=17912666&rft_id=info:pmid/11509024&rft_els_id=S0041008X01992439&rfr_iscdi=true |