Publications (7)12.58 Total impact
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Dataset: hepatobiliary 110221
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Dataset: hepatobiliary 110221
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Dataset: nephrotox 110221
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Article: Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity.
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ABSTRACT: Several novel urinary kidney biomarkers were recently approved by the US-FDA and EMA for improved detection of nephrotoxicity, but few data regarding their performance are publicly available so far. In this study, we investigated the potential of some of the newly accepted makers (Kim-1, β-2-microglobulin, cystatin C, clusterin) along with six additional urinary key proteins of kidney injury (GST-α, Timp-1, VEGF, calbindin, NGAL/lipocalin-2, osteopontin) to detect proximal tubule damage in the rat model studying either acute drug-induced kidney injury or subchronic nephrotoxicity. Candidate proteins were measured in urine samples obtained from rats treated with gentamicin (0, 60 and 120 mg/kg bw for 7 days), BI-3 [3-pyrrolidineacetic acid, 5-[[[4'-[imino[(methoxycarbonyl) amino]methyl] [1,1'-biphenyl]-4-yl]oxy]methyl]-2-oxo-, methyl ester,(3S-trans)] (0, 100, and 1000 mg/kg bw for up to 14 days) or with the mycotoxin ochratoxin A (OTA) (0, 21, 70 and 210 μg/kg bw for up to 90 days) using a Luminex(®) xMAP(®) platform. Cystatin C and NGAL appeared to be the most sensitive indicators of gentamicin nephrotoxicity, with significant changes occurring as early as day 1, and importantly before alterations in serum creatinine or blood urea nitrogen (BUN). Altered urinary excretion of KIM-1, clusterin, calbindin and Timp-1 accompanied by a rise in BUN was observed in rats with BI-3 at 1000 mg/kg bw for 14 days. In contrast, histopathological alterations induced by OTA, which preceded effects on traditional clinical parameters, were best reflected by changes in urinary Kim-1. Overall, our data confirm increased sensitivity of new markers as compared to traditional clinical chemistry parameters.Toxicology 11/2010; 277(1-3):49-58. · 3.68 Impact Factor -
Article: Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers.
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ABSTRACT: The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with "omics" data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.Toxicology and Applied Pharmacology 11/2010; 252(2):112-22. · 4.45 Impact Factor -
Article: The enhanced value of combining conventional and "omics" analyses in early assessment of drug-induced hepatobiliary injury.
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ABSTRACT: 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 14days 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.Toxicology and Applied Pharmacology 09/2010; 252(2):97-111. · 4.45 Impact Factor -
Article: The enhanced value of combining conventional and “omics” analyses in early assessment of drug-induced hepatobiliary injury
[show abstract] [hide abstract]
ABSTRACT: 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.
Top co-authors
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Institutions
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2010
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Universität Würzburg
Würzburg, Bavaria, Germany -
Bayer Pharma AG
Berlin, Land Berlin, Germany
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