The enhanced value of combining conventional and 'omics' analyses in early assessment of drug-induced hepatobiliary injury

Journal Article · Fri Apr 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.09.022· OSTI ID:21538471

Ellinger-Ziegelbauer, Heidrun ^[1]; Adler, Melanie ^[2]; Amberg, Alexander ^[3]; Brandenburg, Arnd ^[4]; Callanan, John J ^[5]; Connor, Susan ^[6]; Fountoulakis, Michael ^[7]; Gmuender, Hans ^[4]; Gruhler, Albrecht ^[8]; Hewitt, Philip ^[9]; Hodson, Mark ^[6]; Matheis, Katja A ^[10]; McCarthy, Diane ^[11]; Raschke, Marian; Riefke, Bjoern ^[12]; Schmitt, Christina S ^[9]; Sieber, Max ^[2]; Sposny, Alexandra ^[9]; Suter, Laura ^[7]; Sweatman, Brian ^[6]

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1. Bayer Schering Pharma AG, Wuppertal (Germany)
2. University of Wuerzburg, Wuerzburg (Germany)
3. Sanofi aventis R and D, Disposition, Safety and Animal Research, Frankfurt (Germany)
4. Genedata AG, Basel (Switzerland)
5. UCD School of Biomolecular and Biomedical Science and School of Agriculture, Food Science and Veterinary Medicine, UCD Conway Institute, University College Dublin, Dublin (Ireland)
6. MetaPro (United Kingdom)
7. Hoffmann-La Roche AG, Basel (Switzerland)
8. Novo Nordisk A/S, Maaloev (Denmark)
9. Merck KGaA Darmstadt (Germany)
10. Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach (Germany)
11. Bio-Rad, Laboratories, Hercules, CA (United States)
12. Bayer Schering Pharma AG, Berlin (Germany)

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.

• OSTI ID: 21538471
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
ALKALINE PHOSPHATASE
AMINO ACIDS
ANIMALS
AZOLES
BILE ACIDS
BILIARY TRACT
BILIRUBIN
BODY
CARBOXYLIC ACIDS
CHROMATOGRAPHY
DIGESTIVE SYSTEM
DISEASES
DOSES
DRUGS
ENZYMES
ESTERASES
FORECASTING
GENES
GLANDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROLASES
HYDROXY COMPOUNDS
INFLAMMATION
INJURIES
LIQUID COLUMN CHROMATOGRAPHY
LIVER
MAMMALS
MASS SPECTROSCOPY
METABOLISM
NECROSIS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PHOSPHATASES
PIGMENTS
PROTEINS
PYRROLES
RATS
RISK ASSESSMENT
RODENTS
SEPARATION PROCESSES
SPECTROSCOPY
STEROIDS
STEROLS
SYMPTOMS
TOXICITY
VERTEBRATES