Toxicogenomics and Classic Toxicology: How to Improve Prediction and Mechanistic Understanding of Human Toxicity

  • Donna L. Mendrick
Part of the Methods in Molecular Biology™ book series (MIMB, volume 460)


The field of toxicogenomics has been advancing during the past decade or so since its origin. Most pharmaceutical companies are using it in one or more ways to improve their productivity and supplement their classic toxicology studies. Acceptance of toxicogenomics will continue to grow as regulatory concerns are addressed, proof of concept studies are disseminated more fully, and internal case studies show value for the use of this new technology in concert with classic testing.

Key Words

hepatocytes hepatotoxicity idiosyncratic phenotypic anchoring toxicogenomics toxicology 


  1. 1.
    Kola, I. and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711–715.CrossRefPubMedGoogle Scholar
  2. 2.
    Mayne, J.T., Ku, W.W., and Kennedy, S.P. (2006) Informed toxicity assessment in drug discovery: systems-based toxicology. Curr. Opin. Drug Discov. Dev. 9, 75–83.Google Scholar
  3. 3.
    Barros, S.A. (2005) The importance of applying toxicogenomics to increase the efficiency of drug discovery. Pharmacogenomics 6, 547–550.CrossRefPubMedGoogle Scholar
  4. 4.
    DiMasi, J.A., Hansen, R.W., and Grabowski, H.G. (2003) The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185.CrossRefPubMedGoogle Scholar
  5. 5.
    Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., et al. (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67.CrossRefPubMedGoogle Scholar
  6. 6.
    Suter, L., Babiss, L.E., and Wheeldon, E.B. (2004) Toxicogenomics in predictive toxicology in drug development. Chem. Biol. 11, 161–171.PubMedGoogle Scholar
  7. 7.
    DiMasi, J.A. (2002) The value of improving the productivity of the drug development process: faster times and better decisions. Pharmacoeconomics 20 (Suppl 3), 1–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Boverhof, D.R. and Zacharewski, T.R. (2006) Toxicogenomics in risk assessment: applications and needs. Toxicol. Sci. 89, 352–360.CrossRefPubMedGoogle Scholar
  9. 9.
    Yang, Y., Blomme, E.A., and Waring, J.F. (2004) Toxicogenomics in drug discovery: from preclinical studies to clinical trials. Chem. Biol. Interact. 150, 71–85.CrossRefPubMedGoogle Scholar
  10. 10.
    Luhe, A., Suter, L., Ruepp, S., Singer, T., Weiser, T., and Albertini, S. (2005) Toxicogenomics in the pharmaceutical industry: hollow promises or real benefit? Mutat. Res. 575, 102–115.PubMedGoogle Scholar
  11. 11.
    Lord, P.G. (2004) Progress in applying genomics in drug development. Toxicol. Lett. 149, 371–375.CrossRefPubMedGoogle Scholar
  12. 12.
    Searfoss, G.H., Ryan, T.P., and Jolly, R.A. (2005) The role of transcriptome analysis in pre-clinical toxicology. Curr. Mol. Med. 5, 53–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Guerreiro, N., Staedtler, F., Grenet, O., Kehren, J., and Chibout, S.D. (2003) Toxicogenomics in drug development. Toxicol. Pathol. 31, 471–479.PubMedGoogle Scholar
  14. 14.
    Dix, D.J., Houck, K.A., Martin, M.T., Richard, A.M., Setzer, R.W., and Kavlock, R.J. (2007) The ToxCast Program for Prioritizing Toxicity Testing of Environmental Chemicals. Toxicol. Sci. 95, 5–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Lord, P.G., Nie, A., and McMillian, M. (2006) Application of genomics in preclinical drug safety evaluation. Basic Clin. Pharmacol. Toxicol. 98, 537–546.CrossRefPubMedGoogle Scholar
  16. 16.
    Shioda, T., Chesnes, J., Coser, K.R., Zou, L., Hur, J., Dean, K.L., et al. (2006) Importance of dosage standardization for interpreting transcriptomal signature profiles: evidence from studies of xenoestrogens. Proc. Natl. Acad. Sci. U. S. A. 103, 12033–12038.CrossRefPubMedGoogle Scholar
  17. 17.
    Farr, S. and Dunn, R.T. II (1999) Concise review: gene expression applied to toxicology. Toxicol. Sci. 50, 1–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Heinloth, A.N., Irwin, R.D., Boorman, G.A., Nettesheim, P., Fannin, R.D., Sieber, S.O., et al. (2004) Gene expression profiling of rat livers reveals indicators of potential adverse effects. Toxicol. Sci. 80, 193–202.CrossRefPubMedGoogle Scholar
  19. 19.
    Nie, A.Y., McMillian, M., Brandon, P.J., Leone, A., Bryant, S., Yieh, L., et al. (2006) Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity. Mol. Carcinog. 45, 914–933.CrossRefPubMedGoogle Scholar
  20. 20.
    Mattes, W.B., Daniels, K.K., Summan, M., Xu, Z.A., and Mendrick, D.L. (2006) Tissue and species distribution of the glutathione pathway transcriptome. Xenobiotica 36, 1081–1121.CrossRefPubMedGoogle Scholar
  21. 21.
    Martin, R., Rose, D., Yu, K., and Barros, S. (2006) Toxicogenomics strategies for predicting drug toxicity. Pharmacogenomics 7, 1003–1016.CrossRefPubMedGoogle Scholar
  22. 22.
    Hultin-Rosenberg, L., Jagannathan, S., Nilsson, K.C., Matis, S.A., Sjogren, N., Huby, R.D., et al. (2006) Predictive models of hepatotoxicity using gene expression data from primary rat hepatocytes. Xenobiotica 36, 1122–1139.CrossRefPubMedGoogle Scholar
  23. 23.
    Kaplowitz, N. (2005) Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. 4, 489–499.CrossRefPubMedGoogle Scholar
  24. 24.
    Dieckhaus, C.M., Miller, T.A., Sofia, R.D., and Macdonald, T.L. (2000) A mechanistic approach to understanding species differences in felbamate bioactivation: relevance to drug-induced idiosyncratic reactions. Drug Metab. Dispos. 28, 814–822.Google Scholar
  25. 25.
    Alden, C., Lin, J., and Smith, P. (2003) Predicting toxicology technology for avoiding idiosyncratic liver injury. Preclinica May/June, 27–35.Google Scholar
  26. 26.
    Popovic, M., Nierkens, S., Pieters, R., and Uetrecht, J. (2004) Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. 17, 1568–1576.CrossRefPubMedGoogle Scholar
  27. 27.
    Ettinger, A.B., Jandorf, L., Berdia, A., Andriola, M.R., Krupp, L.B., and Weisbrot, D.M. (1996) Felbamate-induced headache. Epilepsia 37, 503–505.CrossRefPubMedGoogle Scholar
  28. 28.
    McGee, J.H., Erikson, D.J., Galbreath, C., Willigan, D.A., and Sofia, R.D. (1998) Acute, subchronic, and chronic toxicity studies with felbamate, 2-phenyl-1.,3-propanediol dicarbamate. Toxicol. Sci. 45, 225–232.CrossRefPubMedGoogle Scholar
  29. 29.
    Carvajal Garcia-Pando, A., Garcia, d.P., Sanchez, A.S., Velasco, M.A., Rueda de Castro, A.M., and Lucena, M.I. (2002) Hepatotoxicity associated with the new antidepressants. J. Clin. Psychiatry 63, 135–137.PubMedGoogle Scholar
  30. 30.
    Stewart, D.E. (2002) Hepatic adverse reactions associated with nefazodone. Can. J. Psychiatry 47, 375–377.PubMedGoogle Scholar
  31. 31.
    Choi, S. (2003) Nefazodone (Serzone) withdrawn because of hepatotoxicity. CMAJ. 169, 1187.PubMedGoogle Scholar
  32. 32.
    Aranda-Michel, J., Koehler, A., Bejarano, P.A., Poulos, J.E., Luxon, B.A., Khan, C.M., et al. (1999) Nefazodone-induced liver failure: report of three cases. Ann. Intern. Med. 130, 285–288.PubMedGoogle Scholar
  33. 33.
    Schrader, G.D. and Roberts-Thompson, I.C. (1999) Adverse effect of nefazodone: hepatitis. Med. J. Aust. 170, 452.PubMedGoogle Scholar
  34. 34.
    Kostrubsky, S.E., Strom, S.C., Kalgutkar, A.S., Kulkarni, S., Atherton, J., Mireles, R., et al. (2006) Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90, 451–459.CrossRefPubMedGoogle Scholar
  35. 35.
    Greene, D.S. and Barbhaiya, R.H. (1997) Clinical pharmacokinetics of nefazodone. Clin. Pharmacokinet. 33, 260–275.CrossRefPubMedGoogle Scholar
  36. 36.
    DeVane, C.L., Donovan, J.L., Liston, H.L., Markowitz, J.S., Cheng, K.T., Risch, S.C., and Willard, L. (2004) Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J. Clin. Psychopharmacol. 24, 4–10.CrossRefPubMedGoogle Scholar
  37. 37.
    Kalgutkar, A.S., Vaz, A.D., Lame, M.E., Henne, K.R., Soglia, J., Zhao, S.X., et al. (2005) Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab. Dispos. 33, 243–253.CrossRefPubMedGoogle Scholar
  38. 38.
    Kostrubsky, V.E., Strom, S.C., Hanson, J., Urda, E., Rose, K., Burliegh, J., et al. (2003) Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats. Toxicol. Sci. 76, 220–228.CrossRefPubMedGoogle Scholar
  39. 39.
    Landis, G.N. and Tower, J. (2005) Superoxide dismutase evolution and life span regulation. Mech. Ageing Dev. 126, 365–379.CrossRefPubMedGoogle Scholar
  40. 40.
    Dambach, D.M., Andrews, B.A., and Moulin, F. (2005) New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol. Pathol. 33, 17–26.CrossRefPubMedGoogle Scholar
  41. 41.
    Meador, V., Jordan, W., and Zimmermann, J. (2002) Increasing throughput in lead optimization in vivo toxicity screens. Curr. Opin. Drug Discov. Dev. 5, 72–78.Google Scholar
  42. 42.
    Liguori, M.J., Anderson, L.M., Bukofzer, S., McKim, J., Pregenzer, J.F., Retief, J., et al. (2005) Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin. Hepatology 41, 177–186.CrossRefPubMedGoogle Scholar
  43. 43.
    Waring, J.F., Ciurlionis, R., Jolly, R.A., Heindel, M., and Ulrich, R.G. (2001) Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. Toxicol. Lett. 120, 359–368.CrossRefPubMedGoogle Scholar
  44. 44.
    Sawada, H., Takami, K., and Asahi, S. (2005) A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83, 282–292.CrossRefPubMedGoogle Scholar
  45. 45.
    Reynolds, V.L. (2005) Applications of emerging technologies in toxicology and safety assessment. Int. J. Toxicol. 24, 135–137.CrossRefPubMedGoogle Scholar
  46. 46.
    Shi, L., Reid, L.H., Jones, W.D., Shippy, R., Warrington, J.A., Baker, S.C., et al. (2006) The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat. Biotechnol. 24, 1151–1161.CrossRefPubMedGoogle Scholar
  47. 47.
    Canales, R.D., Luo, Y., Willey, J.C., Austermiller, B., Barbacioru, C.C., Boysen, C., et al. (2006) Evaluation of DNA microarray results with quantitative gene expression platforms. Nat. Biotechnol. 24, 1115–1122.CrossRefPubMedGoogle Scholar
  48. 48.
    Guo, L., Lobenhofer, E.K., Wang, C., Shippy, R., Harris, S.C., Zhang, L., et al. (2006) Rat toxicogenomic study reveals analytical consistency across microarray platforms. Nat. Biotechnol. 24, 1162–1169.CrossRefPubMedGoogle Scholar
  49. 49.
    Goodsaid, F. and Frueh, F. (2006) Process map proposal for the validation of genomic biomarkers. Pharmacogenomics 7, 773–782.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Donna L. Mendrick
    • 1
  1. 1.Department of ToxicogenomicsGene Logic Inc.GaithersburgMaryland

Personalised recommendations