Skip to main content
SpringerLink
Log in

Toxicogenomics applied to predictive and exploratory toxicology for the safety assessment of new chemical entities: a long road with deep potholes

  • Chapter
Systems Biological Approaches in Infectious Diseases

Part of the book series: Progress in Drug Research ((PDR,volume 64))

Abstract

Toxicology is the perturbation of metabolism by external factors such as xenobiotics, environmental factors or drugs. As such, toxicology covers a broad range of fields from studies of the whole organism responses to minute biochemical events. Mechanistic toxicogenomics is an attempt to harness genomic tools to understand the physiological basis for a toxic event based on an analysis of transcriptional, translational or metabolomic profiles. These studies are complicated by non-toxic adaptive responses in transcript, protein or metabolite expression levels that have to be distinguished from those that are proximally related to the toxic event. Substantial progress has been made on the identification of biomarkers and the establishment of screens derived from such toxicogenomics studies. The ultimate goal, of course, is predictive toxicogenomics, which is an attempt to infer the likelihood of occurrence of a toxic event with exposure to a new agent based upon comparative responses with large databases of gene, protein or metabolite expression data. Gene expression databases are currently limited by the fact that measurable toxic phenotypes generally precede or at best coincide with the earliest observable changes in transcriptional profiles. Unfortunately, predictive protein databases have been limited by technical difficulties. Metabonomics-based databases, which would probably have the highest predictive value, are limited in turn by the inability to perform high dose studies in humans. This chapter will conclude by reviewing those elements of toxicogenomics that apply specifically to the development of anti-infectives and the potential for accuratelymodelling the toxicity of future drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Colebatch G, Trevaskis B, Udvardi M (2002) Functional genomics: Tools of the trade. New Phytol 153: 27–36

    Article  CAS  Google Scholar 

  2. Mahler SM, Chin DY, Van Dyk DD (2003) The application of emerging technologies in genomics and proteomics to drug development. J Pharm Pract Res 33: 7–11

    Google Scholar 

  3. van Hall NL, Vorst O, van Houwelingen AM, Kok EJ, Peijnenburg A, Aharoni A, van Tunen AJ, Keijer J (2000) The application of DNA microarray in gene expression analysis. J Biotechnol 78: 271–280

    Article  Google Scholar 

  4. Butte A (2002) The use and analysis of microarray data. Nat Rev Drug Disc 1: 951–960

    Article  CAS  Google Scholar 

  5. Nicholson JK, Wilson ID (2003) Understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat Rev Drug Discov 2: 668–676

    Article  PubMed  CAS  Google Scholar 

  6. De Longueville F, Bertholet V, Remacle J (2004) DNA microarrays as a tool in toxicogenomics. Comb Chem High Throughput Screening 7: 207–211

    Google Scholar 

  7. Witkampt RF (2005) Genomics and system biology — how relevant are the developments to veterinary pharmacology, toxicology and therapeutics? J Vet Pharmacol Therap 28: 235–245

    Article  Google Scholar 

  8. Loferer H, Jacobi A, Posch A, Gauss C, Meier-Ewert S, Seizinger B (2000) Integrated bacterial genomics for the discovery of novel antimicrobials. Drug Discovery Today 5: 107–114

    Article  PubMed  CAS  Google Scholar 

  9. Tugwood JD, Hollins LE, Cockerill MJ (2003) Genomics and the search for novel biomarkers in toxicology. Biomarkers 8: 79–92

    Article  PubMed  CAS  Google Scholar 

  10. Kramer JA, Kolaja K (2002) Toxicogenomics: an opportunity to optimise drug development and safety evaluation. Expert Opin Drug Saf 1: 275–286

    Article  PubMed  CAS  Google Scholar 

  11. Wildsmith S, Spence F (2003) Preparation and utilisation of microarrays. In: ME Burczynski (ed): An introduction to toxicogenomics. CRC Press, Boca Raton, USA, pp 3–16

    Google Scholar 

  12. Li J, Johnson JA (2003) Comparative studies using cDNA vs. oligonucleotide arrays. In: ME Burczynski (ed): An introduction to toxicogenomics. CRC Press, Boca Raton, USA. pp 17–27

    Google Scholar 

  13. Sebastiani P, Gussoni E, Kohane IS, Ramoni MF (2003) Statistical challenges in functional genomics. Stat Sci 18: 33–60

    Article  Google Scholar 

  14. Ge H, Walhout AJ, Vidal M (2003) Integrating ‘omic’ information: a bridge between genomics and systems biology. Trends Genet 19: 551–560

    Article  PubMed  CAS  Google Scholar 

  15. Guerreiro N, Staedtler F, Grenet O, Kehren J, Chibout S-D (2003) Toxicogenomics in drug development. Toxicol Pathol 31: 471–479

    Article  PubMed  CAS  Google Scholar 

  16. Pognan F (2004) Genomics, proteomics and metabonomics in toxicology: Hopefully not ‘fashionomics’. Pharmacogenomics 5: 879–893

    Article  PubMed  CAS  Google Scholar 

  17. Muckter H (2003) What is toxicology and how does it occur? Baillieres Best Pract Res Clin Anaes 17: 5–27

    Article  CAS  Google Scholar 

  18. Chan VSW, Theilade MD (2005) The use of toxicogenomic data in risk assessment: A regulatory perspective. Clin Toxicol 43: 121–126

    CAS  Google Scholar 

  19. Scheel J, von Brevern M-C, Storck T (2003) An overview of mechanistic toxicogenomics studies. In: ME Burczynski (ed): An introduction to toxicogenomics. CRC Press, Boca Raton, USA. pp 183–209

    Google Scholar 

  20. Fountoulakis M, Berndt P, Boelsterli UA, Crameri F, Winter M, Albertini S, Suter L (2000) Two-dimensional database ofmouse liver proteins: Changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3-acetamidophenol. Electrophoresis 21: 2148–2161

    Article  PubMed  CAS  Google Scholar 

  21. Reilly TP, Bourdi M, Brady JN, Pise-Masison CA, Radonovich MF, George JW, Pohl LR (2001) Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem Biophys Res Com 282: 321–328

    Article  PubMed  CAS  Google Scholar 

  22. Ruepp SU, Tonge RP, Shaw J, Wallis N, Pognan F (2002) Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol Sci 65: 135–150

    Article  PubMed  CAS  Google Scholar 

  23. Coen M, Lenz EM, Nicholson JK, Wilson ID, Pognan F, Lindon JC (2003). An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. Chem Res Tox 16: 295–303

    Article  CAS  Google Scholar 

  24. Coen M, Ruepp SU, Lindon JC, Nicholson JK, Pognan F, Lenz EM, Wilson ID (2004) Application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse. J Pharm Biomed Anal 35: 93–105

    Article  PubMed  CAS  Google Scholar 

  25. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, Greenberg B, Ciaccio PJ (2004) Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82: 341–358

    Article  PubMed  CAS  Google Scholar 

  26. Cornwell PD, de Souza AT, Ulrich RG (2004) Profiling of hepatic gene expression in rats treated with fibric acid analogs. Mut Res 549: 131–145

    CAS  Google Scholar 

  27. Peters JM, Cattley RC, Gonzalez FJ (1997) Role of PPAR alpha in the mechanismof action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis 18: 2029–2033

    Article  PubMed  CAS  Google Scholar 

  28. Montenez JP, Van Bambeke F, Piret J, Brasseur R, Tulkens PM, Mingeot-Leclercq MP (1999) Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models. Toxicol Appl Pharmacol 156: 129–140

    Article  PubMed  CAS  Google Scholar 

  29. Casartelli A, Bonato M, Cristofori P, Crivellente F, Dal Negro G, Masotto I, Mutinelli C, Valko K, Bonfante V (2003) A cell-based approach for the early assessment of the phospholipidogenic potential in pharmaceutical research and drug development. Cell Biol Toxicol 19: 161–176

    Article  PubMed  CAS  Google Scholar 

  30. Morelli JK, Buehrle M, Pognan F, Barone L, Fieles W, Ciaccio PJ (2006) Validation of an in vitro screen for phopholipidosis using a high content biology platform. Cell Biol Toxicol 22: 15–27

    Article  PubMed  CAS  Google Scholar 

  31. Sawada H, Takami K, Asahi SA (2005) Toxicogenomic approach to drug-induced phospholipidosis: Analysis of its induction mechanism and establishment of a novel in vitro screening system. Tox Sci 83: 282–292

    Article  CAS  Google Scholar 

  32. Suter L, Babiss LE, Wheeldon EB (2004) Toxicogenomics in predictive toxicology drug development. Chem Biol 11: 161–171

    Article  PubMed  CAS  Google Scholar 

  33. Porter MW, Castle AL, Orr MS, Mendrick DL (2003) Predictive toxicogenomics. In: ME Burczynski (ed): An introduction to toxicogenomics. CRC Press, Boca Raton, USA. pp 183–209

    Google Scholar 

  34. Sherlock G (2000) Analysis of large-scale gene expression data. Curr Opin Immunol 12: 201–205

    Article  PubMed  CAS  Google Scholar 

  35. Joliffe IT, Morgan BJ (1992) Principal component analysis and exploratory factor analysis. Stat Methods Med Res 1: 69–95

    PubMed  CAS  Google Scholar 

  36. Waring JF, Jolly RA, Ciurlionis R, Lum PY, Praestgaard JT, Morfitt DC, Buratto B, Roberts C, Schadt E, Ulrich RG (2001) Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol Appl Pharmacol 175: 28–42

    Article  PubMed  CAS  Google Scholar 

  37. Mattes WB, Pettit SD, Sansone S-A, Bushel PR, Waters MD (2004) Database development in toxicogenomics: Issues and efforts. Environ Health Perspect 112: 495–505

    PubMed  CAS  Google Scholar 

  38. Hayes KR, Vollrath AL, Zastrow GM, McMillan BJ, Craven M, Jovanovich S, Rank DR, Penn S, Walisser JA, Reddy JK et al (2005) EDGE: A centralized resource for the comparison, analysis, and distribution of toxicogenomic information. Mol Pharmacol 67: 1360–1368

    Article  PubMed  CAS  Google Scholar 

  39. Huby R, Tugwood JD (2005) Gene expression profiling for pharmaceutical safety assessment. Expert Opin Drug Metab Toxicol 1: 247–260

    Article  PubMed  CAS  Google Scholar 

  40. Klaassen CD (ed) (2001) Casarett and Doull’s toxicology: the basic science of poisons. Sixth Edition. McGraw-Hill, New York, USA

    Google Scholar 

  41. Luhe A, Suter L, Ruepp S, Singer T, Weiser T, Albertini S (2005) Toxicogenomics in the pharmaceutical industry: Hollow promises or real benefit? Mut Res 575: 102–115

    Google Scholar 

  42. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W et al (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32: 56–67

    Article  PubMed  CAS  Google Scholar 

  43. Bollard ME, Holmes E, Lindon JC, Mitchell SC, Branstetter D, Zhang W, Nicholson JK (2001) Investigations into biochemical changes due to diurnal variation and estrus cycle in female rats using high-resolution (1)H NMR spectroscopy of urine and pattern recognition. Anal Biochem 295: 194–202

    Article  PubMed  CAS  Google Scholar 

  44. Wang Y, Tang H, Nicholson JK, Hylands PJ, Sampson J, Holmes E (2005) A metabonomic strategy for the detection of the metabolic effects of chamomile (Matricaria recutita L.) ingestion. J Agric Food Chem 53: 191–196

    Article  PubMed  CAS  Google Scholar 

  45. Boess F, Kamber M, Romer S, Gasser R, Muller D, Albertini S, Suter L (2003) 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. Toxicol Sci 73: 386–402

    Article  PubMed  CAS  Google Scholar 

  46. Kier LD, Neft R, Tang L, Suizu R, Cook T, Onsurez K, Tiegler K, Sakai Y, Ortiz M, Nolan T et al (2004) Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro. Mutat Res 549: 101–113

    PubMed  CAS  Google Scholar 

  47. de Backer MD, van Dijck P (2003) Progress in functional genomics approaches to antifungal drug target discovery. Trends in Microbiol 11: 470–478

    Article  CAS  Google Scholar 

  48. Parkinson T (2002) The impact of genomics on anti-infectives drugs discovery and development. Trends in Microbiol 10: S22–26

    Article  CAS  Google Scholar 

  49. Contreras A, Barbacid M, Vazquez D (1974) Binding to ribosomes and mode of action of chloramphenicol analogues. Biochim Biophys Acta 349: 376–388

    PubMed  CAS  Google Scholar 

  50. Matassova NB, Rodnina MV, Endermann R, Kroll HP, Pleiss U, Wild H, Wintermeyer W (1999) Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors. RNA 5: 939–946

    Article  PubMed  CAS  Google Scholar 

  51. Turton JA, Yallop D, Andrews CM, Fagg R, York M, Williams TC (1999) Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat. Hum Exp Toxicol 18: 566–576

    Article  PubMed  CAS  Google Scholar 

  52. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, Kuter DJ. (2002) Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 46: 2723–2726

    Article  PubMed  CAS  Google Scholar 

  53. Xu J, Gordon JI (2003) Honor thy symbionts. Proc Natl Acad Sci USA 100: 10452–10459

    Article  PubMed  CAS  Google Scholar 

  54. Nicholson JK, Holmes E, Wilson ID (2005) Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol 3: 431–438

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Safety Assessment, AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK

    François Pognan

Authors
  1. François Pognan
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Tuberculosis Research Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20852, USA

    Helena I. Boshoff  & Clifton E. Barry III  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Birkhäuser Verlag

About this chapter

Cite this chapter

Pognan, F. (2007). Toxicogenomics applied to predictive and exploratory toxicology for the safety assessment of new chemical entities: a long road with deep potholes. In: Boshoff, H.I., Barry, C.E. (eds) Systems Biological Approaches in Infectious Diseases. Progress in Drug Research, vol 64. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-7567-6_9

Download citation

Publish with us

Policies and ethics

Search

Navigation