The enhanced value of combining conventional and 'omics' analyses in early assessment of drug-induced hepatobiliary injury
| Autor: | Heidrun Ellinger-Ziegelbauer, Brian C. Sweatman, John J. Callanan, Marian Raschke, Mark P. Hodson, Angela Mally, Arnd Brandenburg, Katja Matheis, Alexandra Sposny, Hans Gmuender, Diane McCarthy, Laura Suter, Björn Riefke, Albrecht Gruhler, Susan C. Connor, Alexander Amberg, Christina S. Schmitt, Max Sieber, Melanie Adler, Michael Fountoulakis, Philip Hewitt |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Proteomics Pathology medicine.medical_specialty Drug-Related Side Effects and Adverse Reactions medicine.drug_class Cholestasis Intrahepatic Pharmacology Biology Toxicology Cholestasis medicine Animals Metabolomics Rats Wistar Bile acid Bile duct Gene Expression Profiling medicine.disease Rats medicine.anatomical_structure Biliary tract Hepatocyte Toxicity Chemical and Drug Induced Liver Injury Toxicogenomics |
| Zdroj: | Toxicology and applied pharmacology. 252(2) |
| ISSN: | 1096-0333 |
| Popis: | The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling (" omics" ) technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14. days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics. © 2010 Elsevier Inc. |
| Databáze: | OpenAIRE |
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