Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics
This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BL...
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| Veröffentlicht in: | International journal of toxicology 2011-05, Vol.30 (3), p.300-312 |
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| creator | Wang, Tao Papoutsi, Maria Wiesmann, Marion DeCristofaro, Marc Keselica, M. Craig Skuba, Elizabeth Spaet, Robert Markovits, Judit Wolf, Armin Moulin, Pierre Pognan, Francois Vancutsem, Paul Petryk, Lew Sutton, James Chibout, Salah-Dine Kluwe, William |
| description | This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations. |
| doi_str_mv | 10.1177/1091581811401920 |
| format | Article |
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Craig ; Skuba, Elizabeth ; Spaet, Robert ; Markovits, Judit ; Wolf, Armin ; Moulin, Pierre ; Pognan, Francois ; Vancutsem, Paul ; Petryk, Lew ; Sutton, James ; Chibout, Salah-Dine ; Kluwe, William</creator><creatorcontrib>Wang, Tao ; Papoutsi, Maria ; Wiesmann, Marion ; DeCristofaro, Marc ; Keselica, M. Craig ; Skuba, Elizabeth ; Spaet, Robert ; Markovits, Judit ; Wolf, Armin ; Moulin, Pierre ; Pognan, Francois ; Vancutsem, Paul ; Petryk, Lew ; Sutton, James ; Chibout, Salah-Dine ; Kluwe, William</creatorcontrib><description>This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.</description><identifier>ISSN: 1091-5818</identifier><identifier>EISSN: 1092-874X</identifier><identifier>DOI: 10.1177/1091581811401920</identifier><identifier>PMID: 21653914</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Alanine Transaminase - blood ; Alanine Transaminase - genetics ; Animals ; Aspartate Aminotransferases - blood ; Aspartate Aminotransferases - genetics ; Benzothiazoles - toxicity ; Biomarkers - blood ; Down-Regulation - drug effects ; Gene Expression Profiling ; Humans ; Liver - drug effects ; Liver - enzymology ; Liver - pathology ; Macaca fascicularis ; Pharmacogenetics ; Picolinic Acids - toxicity ; Rats ; Rats, Wistar ; RNA, Messenger - genetics ; Toxicity Tests ; Up-Regulation - drug effects</subject><ispartof>International journal of toxicology, 2011-05, Vol.30 (3), p.300-312</ispartof><rights>The Author(s) 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c336t-4cb8e4b68d82643a84d3d97a1b15096f3b9059b17c7ec59ab7314b49f0e968cc3</citedby><cites>FETCH-LOGICAL-c336t-4cb8e4b68d82643a84d3d97a1b15096f3b9059b17c7ec59ab7314b49f0e968cc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/1091581811401920$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/1091581811401920$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,780,784,21818,27923,27924,43620,43621</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21653914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Tao</creatorcontrib><creatorcontrib>Papoutsi, Maria</creatorcontrib><creatorcontrib>Wiesmann, Marion</creatorcontrib><creatorcontrib>DeCristofaro, Marc</creatorcontrib><creatorcontrib>Keselica, M. Craig</creatorcontrib><creatorcontrib>Skuba, Elizabeth</creatorcontrib><creatorcontrib>Spaet, Robert</creatorcontrib><creatorcontrib>Markovits, Judit</creatorcontrib><creatorcontrib>Wolf, Armin</creatorcontrib><creatorcontrib>Moulin, Pierre</creatorcontrib><creatorcontrib>Pognan, Francois</creatorcontrib><creatorcontrib>Vancutsem, Paul</creatorcontrib><creatorcontrib>Petryk, Lew</creatorcontrib><creatorcontrib>Sutton, James</creatorcontrib><creatorcontrib>Chibout, Salah-Dine</creatorcontrib><creatorcontrib>Kluwe, William</creatorcontrib><title>Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics</title><title>International journal of toxicology</title><addtitle>Int J Toxicol</addtitle><description>This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.</description><subject>Alanine Transaminase - blood</subject><subject>Alanine Transaminase - genetics</subject><subject>Animals</subject><subject>Aspartate Aminotransferases - blood</subject><subject>Aspartate Aminotransferases - genetics</subject><subject>Benzothiazoles - toxicity</subject><subject>Biomarkers - blood</subject><subject>Down-Regulation - drug effects</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Macaca fascicularis</subject><subject>Pharmacogenetics</subject><subject>Picolinic Acids - toxicity</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>RNA, Messenger - genetics</subject><subject>Toxicity Tests</subject><subject>Up-Regulation - drug effects</subject><issn>1091-5818</issn><issn>1092-874X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kDtPwzAUhS0EouWxMyFvLA34Nk5sj6XiUakSAyCxRY7jBJfELnaC2n9P-oABien6Xn_nSOcgdAHkGoCxGyACEg4cgBIQY3KAhv1pHHFG3w63b4g2_wN0EsKCEJKyBI7RYAxpEgugQ7Sc2S8dWlPJ1jiLXYmnzntd79ZJ42yFn2Wp2zW-Na6R_kP7gI3Fz9p3zQg_mtC6pWzfXe0qo2SN71ayMXarH2FpC_ziVka5SlvXGBXO0FEp66DP9_MUvd7fvUwfo_nTw2w6mUcqjtM2oirnmuYpL_g4pbHktIgLwSTkkBCRlnEuSCJyYIpplQiZsxhoTkVJtEi5UvEputr5Lr377PqIWWOC0nUtrXZdyDjjHBhNWE-SHam8C8HrMlt60yddZ0CyTc3Z35p7yeXevMsbXfwKfnrtgWgHBFnpbOE6b_uw_xt-A1b5hhs</recordid><startdate>201105</startdate><enddate>201105</enddate><creator>Wang, Tao</creator><creator>Papoutsi, Maria</creator><creator>Wiesmann, Marion</creator><creator>DeCristofaro, Marc</creator><creator>Keselica, M. Craig</creator><creator>Skuba, Elizabeth</creator><creator>Spaet, Robert</creator><creator>Markovits, Judit</creator><creator>Wolf, Armin</creator><creator>Moulin, Pierre</creator><creator>Pognan, Francois</creator><creator>Vancutsem, Paul</creator><creator>Petryk, Lew</creator><creator>Sutton, James</creator><creator>Chibout, Salah-Dine</creator><creator>Kluwe, William</creator><general>SAGE Publications</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><scope>7X8</scope></search><sort><creationdate>201105</creationdate><title>Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics</title><author>Wang, Tao ; Papoutsi, Maria ; Wiesmann, Marion ; DeCristofaro, Marc ; Keselica, M. Craig ; Skuba, Elizabeth ; Spaet, Robert ; Markovits, Judit ; Wolf, Armin ; Moulin, Pierre ; Pognan, Francois ; Vancutsem, Paul ; Petryk, Lew ; Sutton, James ; Chibout, Salah-Dine ; Kluwe, William</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c336t-4cb8e4b68d82643a84d3d97a1b15096f3b9059b17c7ec59ab7314b49f0e968cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alanine Transaminase - blood</topic><topic>Alanine Transaminase - genetics</topic><topic>Animals</topic><topic>Aspartate Aminotransferases - blood</topic><topic>Aspartate Aminotransferases - genetics</topic><topic>Benzothiazoles - toxicity</topic><topic>Biomarkers - blood</topic><topic>Down-Regulation - drug effects</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Macaca fascicularis</topic><topic>Pharmacogenetics</topic><topic>Picolinic Acids - toxicity</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>RNA, Messenger - genetics</topic><topic>Toxicity Tests</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Tao</creatorcontrib><creatorcontrib>Papoutsi, Maria</creatorcontrib><creatorcontrib>Wiesmann, Marion</creatorcontrib><creatorcontrib>DeCristofaro, Marc</creatorcontrib><creatorcontrib>Keselica, M. 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Craig</au><au>Skuba, Elizabeth</au><au>Spaet, Robert</au><au>Markovits, Judit</au><au>Wolf, Armin</au><au>Moulin, Pierre</au><au>Pognan, Francois</au><au>Vancutsem, Paul</au><au>Petryk, Lew</au><au>Sutton, James</au><au>Chibout, Salah-Dine</au><au>Kluwe, William</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics</atitle><jtitle>International journal of toxicology</jtitle><addtitle>Int J Toxicol</addtitle><date>2011-05</date><risdate>2011</risdate><volume>30</volume><issue>3</issue><spage>300</spage><epage>312</epage><pages>300-312</pages><issn>1091-5818</issn><eissn>1092-874X</eissn><abstract>This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>21653914</pmid><doi>10.1177/1091581811401920</doi><tpages>13</tpages></addata></record> |
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| identifier | ISSN: 1091-5818 |
| ispartof | International journal of toxicology, 2011-05, Vol.30 (3), p.300-312 |
| issn | 1091-5818 1092-874X |
| language | eng |
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| source | MEDLINE; SAGE Complete A-Z List; Alma/SFX Local Collection |
| subjects | Alanine Transaminase - blood Alanine Transaminase - genetics Animals Aspartate Aminotransferases - blood Aspartate Aminotransferases - genetics Benzothiazoles - toxicity Biomarkers - blood Down-Regulation - drug effects Gene Expression Profiling Humans Liver - drug effects Liver - enzymology Liver - pathology Macaca fascicularis Pharmacogenetics Picolinic Acids - toxicity Rats Rats, Wistar RNA, Messenger - genetics Toxicity Tests Up-Regulation - drug effects |
| title | Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics |
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