Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development
Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol...
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| Veröffentlicht in: | Toxicologic pathology 2009-08, Vol.37 (5), p.617-628 |
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| creator | Engle, Steven K. Jordan, William H. Pritt, Michael L. Chiang, Alan Y. Davis, Myrtle A. Zimmermann, John L. Rudmann, Daniel G. Heinz-Taheny, Kathleen M. Irizarry, Armando R. Yamamoto, Yumi Mendel, David Schultze, A. Eric Cornwell, Paul D. Watson, David E. |
| description | Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure–activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery. |
| doi_str_mv | 10.1177/0192623309339502 |
| format | Article |
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Eric ; Cornwell, Paul D. ; Watson, David E.</creator><creatorcontrib>Engle, Steven K. ; Jordan, William H. ; Pritt, Michael L. ; Chiang, Alan Y. ; Davis, Myrtle A. ; Zimmermann, John L. ; Rudmann, Daniel G. ; Heinz-Taheny, Kathleen M. ; Irizarry, Armando R. ; Yamamoto, Yumi ; Mendel, David ; Schultze, A. Eric ; Cornwell, Paul D. ; Watson, David E.</creatorcontrib><description>Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure–activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.</description><identifier>ISSN: 0192-6233</identifier><identifier>EISSN: 1533-1601</identifier><identifier>DOI: 10.1177/0192623309339502</identifier><identifier>PMID: 19549929</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Animals ; Aspartate Aminotransferases - blood ; Biological and medical sciences ; Biomarkers - blood ; Cardiotonic Agents - toxicity ; Creatine Kinase - antagonists & inhibitors ; Creatine Kinase - blood ; Dose-Response Relationship, Drug ; Drug Discovery - methods ; Fatty Acid Binding Protein 3 ; Fatty Acid-Binding Proteins - blood ; Female ; Heart Diseases - blood ; Heart Diseases - chemically induced ; Heart Ventricles - drug effects ; Histocytochemistry ; Inflammation - metabolism ; Isoproterenol - toxicity ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Myocardium - metabolism ; Myocardium - pathology ; Necrosis ; Protein Kinase Inhibitors - toxicity ; Toxicology ; Troponin I - blood</subject><ispartof>Toxicologic pathology, 2009-08, Vol.37 (5), p.617-628</ispartof><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c397t-d0959e3663b6f508a9ee533be22c4994c70d93e75ee0317afc37d4b359e7b4aa3</citedby><cites>FETCH-LOGICAL-c397t-d0959e3663b6f508a9ee533be22c4994c70d93e75ee0317afc37d4b359e7b4aa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/0192623309339502$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/0192623309339502$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,776,780,21798,27901,27902,43597,43598</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21789926$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19549929$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Engle, Steven K.</creatorcontrib><creatorcontrib>Jordan, William H.</creatorcontrib><creatorcontrib>Pritt, Michael L.</creatorcontrib><creatorcontrib>Chiang, Alan Y.</creatorcontrib><creatorcontrib>Davis, Myrtle A.</creatorcontrib><creatorcontrib>Zimmermann, John L.</creatorcontrib><creatorcontrib>Rudmann, Daniel G.</creatorcontrib><creatorcontrib>Heinz-Taheny, Kathleen M.</creatorcontrib><creatorcontrib>Irizarry, Armando R.</creatorcontrib><creatorcontrib>Yamamoto, Yumi</creatorcontrib><creatorcontrib>Mendel, David</creatorcontrib><creatorcontrib>Schultze, A. Eric</creatorcontrib><creatorcontrib>Cornwell, Paul D.</creatorcontrib><creatorcontrib>Watson, David E.</creatorcontrib><title>Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development</title><title>Toxicologic pathology</title><addtitle>Toxicol Pathol</addtitle><description>Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. 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Eric</creatorcontrib><creatorcontrib>Cornwell, Paul D.</creatorcontrib><creatorcontrib>Watson, David E.</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>Toxicologic pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Engle, Steven K.</au><au>Jordan, William H.</au><au>Pritt, Michael L.</au><au>Chiang, Alan Y.</au><au>Davis, Myrtle A.</au><au>Zimmermann, John L.</au><au>Rudmann, Daniel G.</au><au>Heinz-Taheny, Kathleen M.</au><au>Irizarry, Armando R.</au><au>Yamamoto, Yumi</au><au>Mendel, David</au><au>Schultze, A. Eric</au><au>Cornwell, Paul D.</au><au>Watson, David E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development</atitle><jtitle>Toxicologic pathology</jtitle><addtitle>Toxicol Pathol</addtitle><date>2009-08-01</date><risdate>2009</risdate><volume>37</volume><issue>5</issue><spage>617</spage><epage>628</epage><pages>617-628</pages><issn>0192-6233</issn><eissn>1533-1601</eissn><abstract>Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure–activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>19549929</pmid><doi>10.1177/0192623309339502</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Toxicologic pathology, 2009-08, Vol.37 (5), p.617-628 |
| issn | 0192-6233 1533-1601 |
| language | eng |
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| subjects | Animals Aspartate Aminotransferases - blood Biological and medical sciences Biomarkers - blood Cardiotonic Agents - toxicity Creatine Kinase - antagonists & inhibitors Creatine Kinase - blood Dose-Response Relationship, Drug Drug Discovery - methods Fatty Acid Binding Protein 3 Fatty Acid-Binding Proteins - blood Female Heart Diseases - blood Heart Diseases - chemically induced Heart Ventricles - drug effects Histocytochemistry Inflammation - metabolism Isoproterenol - toxicity Medical sciences Mice Mice, Inbred BALB C Myocardium - metabolism Myocardium - pathology Necrosis Protein Kinase Inhibitors - toxicity Toxicology Troponin I - blood |
| title | Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development |
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