Development of a DNA Microarray for Toxicology Based on Hepatotoxin- regulated Sequences

Waring, Jeffrey F.; Cavet, Guy; Jolly, Robert A.; McDowell, Jeff; Dai, Hongye; Ciurlionis, Rita; Zhang, Chunsheng; Stoughton, Roland; Lum, Pek Yee; Ferguson, A. R.; Roberts, Christopher J.; Ulrich, Roger G.

doi:10.1289/txg.5998

Cited by 7 publications

(11 citation statements)

References 3 publications

(4 reference statements)

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“…The challenge for predictive toxicology is to link changes in gene and protein expression to sequential changes in phenotype, both adaptive and adverse, in a manner that is consistent with the underlying biologic mechanisms. For example, gene expression profiling has been used to classify hepatotoxins based on mechanism of action and to differentiate early, presumably adaptive, responses from later responses that are reflective of toxicity ( Hamadeh et al 2002a , 2002b ; Waring et al 2001 , 2003 ). The gene expression changes correlated well with changes in histopathology and clinical chemistry, supporting the liver as target organ for the test compounds.…”

Section: Validation Of Toxicogenomics: Focus On the Biological Systemmentioning

confidence: 99%

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

Corvi

Ahr

Albertini

et al. 2006

Environ Health Perspect

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This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities.

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Section: Validation Of Toxicogenomics: Focus On the Biological Systemmentioning

confidence: 99%

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

Corvi

Ahr

Albertini

et al. 2006

Environ Health Perspect

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“…selected as described in Waring et al (2003). Cy3 or Cy5 labeled cRNA was created from total RNA using reverse transcription (RT) followed by in vitro transcription (IVT) and a 2-step label incorporation method (Hughes et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

Cornwell

Ulrich²

2007

Toxicol Pathol

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A compendium of hepatic gene expression signatures was used to identify a mechanistic basis for the hepatic toxicity of an experimental CCR5 antagonist (MrkA). Development of MrkA, a potential HIV therapeutic, was discontinued due to hepatotoxicity in preclinical studies. Rats were treated with MrkA at 3 dose levels (50, 250, and 500 mg/kg) for 1, 3, or 7 days. Hepatic toxicity (vacuolation, consistent with steatosis, and elevated serum transaminase levels) was observed at 250 and 500 mg/kg, but not at 50 mg/kg. Hepatic gene expression profiles were compared to a compendium of hepatic expression profiles. MrkA was similar to 3 beta-oxidation inhibitors (valproate, cyclopropane carboxylate, pivalate), 8 PPARalpha agonists (fenofibrate, bezafibrate and 6 fibrate analogues), and 3 other diverse compounds (diethylnitrosamine, microcystin LR & actinomycin D). These data indicate MrkA to be a mitochondrial inhibitor, and activation of PPARalpha-regulated transcription was thought to be due to an accumulation of endogenous ligands. While mitochondrial inhibition was likely responsible for steatosis, canonical pathway analysis revealed that progression to liver injury may be mediated by activation of the innate immune system primarily through NF-kB pathways. These results demonstrate the utility of a gene expression response compendium in developing transcriptional biomarkers and identifying the mechanistic basis for toxicity.

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“…Drug toxicity studies are numerous and include effects induced by clofibrate, PPAR alpha agonists, carbon tetrachloride, amiodarone, arsenic and methotrexate [117,125-134]. In one study, a novel cDNA library highly enriched for genes expressed under a variety of hepatotoxic conditions was created and used to develop a custom oligonucleotide library [135]. …”

Section: Gene Array Analysismentioning

confidence: 99%

The hepatic transcriptome in human liver disease

et al. 2006

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The transcriptome is the mRNA transcript pool in a cell, organ or tissue with the liver transcriptome being amongst the most complex of any organ. Functional genomics methodologies are now being widely utilized to study transcriptomes including the hepatic transcriptome. This review outlines commonly used methods of transcriptome analysis, especially gene array analysis, focusing on publications utilizing these methods to understand human liver disease. Additionally, we have outlined the relationship between transcript and protein expressions as well as summarizing what is known about the variability of the transcriptome in non-diseased liver tissue. The approaches covered include gene array analysis, serial analysis of gene expression, subtractive hybridization and differential display. The discussion focuses on primate whole organ studies and in-vitro cell culture systems utilized. It is now clear that there are a vast number research opportunities for transcriptome analysis of human liver disease as we attempt to better understand both non-diseased and disease hepatic mRNA expression. We conclude that hepatic transcriptome analysis has already made significant contributions to the understanding of human liver pathobiology.

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Development of a DNA Microarray for Toxicology Based on Hepatotoxin- regulated Sequences

Abstract: Abbreviations: ip, intraperitoneal; iv, intravenous; ND, not done. a All animals in this treatment group died before day 3 and were not used. Where no reference is provided, dose levels were selected from unpublished results.

Cited by 7 publications

References 3 publications

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

The hepatic transcriptome in human liver disease

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