Toxicogenomics in predictive toxicology in drug development.

The goal of toxicology is the assessment of possible risk to man. An emerging technology with the potential to have a major impact on risk assessment is toxicogenomics. In this review, we provide an overview of the many possibilities for toxicogenomics including technology platforms, data interpretation, and regulatory perspective and we give examples of toxicogenomics investigations. Toxicogenomics is a powerful tool for compound classification, for mechanistic studies, and for the detection of toxicity markers. Thus, toxicogenomics helps in the extrapolation of findings across species and increases predictability. Biomarkers are valuable in the evaluation of compounds at earlier development phases, improving clinical candidate selection. Caution regarding the interpretation of the results is still necessary. Nevertheless, toxicogenomics will accelerate preclinical safety assessments and improve the prediction of toxic liabilities, as well as of potential risk accumulation for drug-drug or drug-disease interactions.

[1]  D. Witiak,et al.  In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat. Structure-activity relationships. , 1990, Biochemical pharmacology.

[2]  Joshua M. Stuart,et al.  MICROARRAY EXPERIMENTS : APPLICATION TO SPORULATION TIME SERIES , 1999 .

[3]  R G Ulrich,et al.  Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. , 2001, Toxicology letters.

[4]  William Pennie,et al.  Toxicogenomics in risk assessment: an overview of an HESI collaborative research program. , 2004, Environmental health perspectives.

[5]  J. Emery,et al.  Unique gene expression patterns in liver and kidney associated with exposure to chemical toxicants. , 2001, The Journal of pharmacology and experimental therapeutics.

[6]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[7]  Lee Bennett,et al.  Gene expression analysis reveals chemical-specific profiles. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[8]  T. Zacharewski,et al.  Workshop overview: use of genomic data in risk assessment. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  Paul G Gauger,et al.  Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. , 2003, The American journal of pathology.

[10]  Marilyn J. Aardema,et al.  Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies. , 2002 .

[11]  J. Ott,et al.  Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity , 2002, The Pharmacogenomics Journal.

[12]  J. Waring,et al.  Clofibrate-induced gene expression changes in rat liver: a cross-laboratory analysis using membrane cDNA arrays. , 2004, Environmental health perspectives.

[13]  Lee Bennett,et al.  Prediction of compound signature using high density gene expression profiling. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Jeffrey A. Kramer,et al.  Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate , 2003, Toxicologic pathology.

[16]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[17]  T. Dingermann,et al.  A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  Stephen H. Friend,et al.  Toxicogenomics and drug discovery: will new technologies help us produce better drugs? , 2002, Nature Reviews Drug Discovery.

[19]  R. Ulrich,et al.  Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression. , 2004, Environmental health perspectives.

[20]  J. Waring,et al.  Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene. , 2004, Environmental health perspectives.

[21]  I. Alvarado,et al.  Advances in the pharmacogenomics of adverse drug reactions , 2002, The Pharmacogenomics Journal.

[22]  S. Albertini,et al.  Effect of two 5-HT6 receptor antagonists on the rat liver: a molecular approach , 2003, The Pharmacogenomics Journal.

[23]  Kerry Blanchard,et al.  Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations , 2002, Toxicologic pathology.

[24]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[25]  Christian A. Rees,et al.  Systematic variation in gene expression patterns in human cancer cell lines , 2000, Nature Genetics.

[26]  Michael D Waters,et al.  Database development in toxicogenomics: issues and efforts. , 2004, Environmental health perspectives.

[27]  W. Alvord,et al.  Microarray analysis of altered gene expression in the TM4 Sertoli-like cell line exposed to chromium(III) chloride. , 2002, Reproductive toxicology.

[28]  G. S. Johnson,et al.  An Information-Intensive Approach to the Molecular Pharmacology of Cancer , 1997, Science.

[29]  Shiew-Mei Huang,et al.  Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Decision Making: Report of the First FDA‐PWG‐PhRMA‐DruSafe Workshop , 2003, Journal of clinical pharmacology.

[30]  Timothy A Bertram,et al.  Identification of putative gene based markers of renal toxicity. , 2004, Environmental health perspectives.

[31]  K. Tomer,et al.  Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643. , 2003, Carcinogenesis.

[32]  J. Reindel,et al.  RNA expression in the early characterization of hepatotoxicants in Wistar rats by high‐density DNA microarrays , 2001, Hepatology.

[33]  K. Wassermann,et al.  Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists. , 2003, Journal of molecular endocrinology.

[34]  S. Steiner,et al.  Expression profiling in toxicology--potentials and limitations. , 2000, Toxicology letters.

[35]  Geoffrey J McLachlan,et al.  Selection bias in gene extraction on the basis of microarray gene-expression data , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Magnuson,et al.  Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology , 2003, The Pharmacogenomics Journal.

[37]  D. Botstein,et al.  A gene expression database for the molecular pharmacology of cancer , 2000, Nature Genetics.

[38]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[39]  M. Oh,et al.  Issues in cDNA microarray analysis: quality filtering, channel normalization, models of variations and assessment of gene effects. , 2001, Nucleic acids research.

[40]  Quantitative PCR deconstruction of discrepancies between results reported by different hybridization platforms. , 2004, Environmental health perspectives.

[41]  Syril D. Pettit,et al.  Use of Genomics in Mechanism Based Risk Assessment , 2003 .

[42]  P. S. Pine,et al.  Dye bias correction in dual-labeled cDNA microarray gene expression measurements. , 2004, Environmental health perspectives.

[43]  Howard L McLeod,et al.  Cancer pharmacogenomics: current and future applications. , 2003, Biochimica et biophysica acta.

[44]  Atul Butte,et al.  The use and analysis of microarray data , 2002, Nature Reviews Drug Discovery.

[45]  Silvio Albertini,et al.  Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[46]  Robert P Tonge,et al.  Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[47]  Ying Zhang,et al.  Block principal component analysis with application to gene microarray data classification , 2002, Statistics in medicine.

[48]  L. Staudt,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[49]  Lee Bennett,et al.  Genomic interrogation of mechanism(s) underlying cellular responses to toxicants. , 2002, Toxicology.

[50]  R E Stoll,et al.  Assessment of cisplatin-induced nephrotoxicity by microarray technology. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[51]  E. Oren,et al.  Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. , 2001, JAMA.

[52]  P. Corey,et al.  Incidence of Adverse Drug Reactions in Hospitalized Patients , 2012 .

[53]  Shibing Deng,et al.  Cross-site comparison of gene expression data reveals high similarity. , 2004, Environmental health perspectives.

[54]  B. Schölkopf,et al.  Advances in kernel methods: support vector learning , 1999 .

[55]  K. Morgan.  Gene expression analysis reveals chemical-specific profiles. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[56]  Silvio Albertini,et al.  Modulation of gene and protein expression by carbon tetrachloride in the rat liver. , 2002, Toxicology and applied pharmacology.

[57]  Jiri Aubrecht,et al.  The utility of DNA microarrays for characterizing genotoxicity. , 2004, Environmental health perspectives.

[58]  K. Thompson,et al.  Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment. , 2004, Environmental health perspectives.

[59]  Frank D Sistare,et al.  Identification of platform-independent gene expression markers of cisplatin nephrotoxicity. , 2004, Environmental health perspectives.

[60]  W. Mattes.  Annotation and cross-indexing of array elements on multiple platforms. , 2004, Environmental health perspectives.

[61]  Jason E. Stewart,et al.  Minimum information about a microarray experiment (MIAME)—toward standards for microarray data , 2001, Nature Genetics.