Skip to main content
SpringerLink
Log in

Toxicogenomics-Based Assessment of Xenobiotic-Induced Oxidative Stress

  • Chapter
Studies on Experimental Toxicology and Pharmacology

  • 1257 Accesses

Abstract

Stress response pathways such as the Nrf2 oxidative stress response have been identified as toxicity pathways (National Research Council (U.S.). Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology (2007) Applications of toxicogenomic technologies to predictive toxicology and risk assessment. Washington, DC). Toxicogenomics-based analyses have been successfully used to causally link activation of this pathway to drug-induced hepatotoxicity. This is a simplistic view and does not take into account the implicit protective nature of this pathway. A clear understanding of the translation of Nrf2 activation to hepatotoxicity is lacking, in part due to the biased selection of known hepatotoxicants in published studies. In drug development in particular, the relevant question is whether or not there will be an adverse cellular outcome. Toxicogenomic monitoring of Nrf2 activation continues to hold great potential to answer this question. However, in addition to assessing the cellular response, identification of gene expression changes indicative of the cellular outcome are necessary in order to truly understand whether or not toxicity will occur. Future studies on gene expression changes following treatment with compounds that demonstrate a chronic vs. transient Nrf2 activation along with phenotypic anchoring could provide useful information regarding restorative or pathological mechanisms following oxidative insult.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

References

  1. Temple RJ, Himmel MH (2002) Safety of newly approved drugs: implications for prescribing. JAMA 287(17):2273–2275

    Article  PubMed  Google Scholar 

  2. Kaplowitz N (2001) Drug-induced liver disorders: implications for drug development and regulation. Drug Saf 24(7):483–490

    Article  CAS  PubMed  Google Scholar 

  3. Lee WM (2003) Acute liver failure in the United States. Semin Liver Dis 23(3):217–226

    Article  CAS  PubMed  Google Scholar 

  4. Ostapowicz G et al (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137(12):947–954

    Article  PubMed  Google Scholar 

  5. Schuster D, Laggner C, Langer T (2005) Why drugs fail–a study on side effects in new chemical entities. Curr Pharm Des 11(27):3545–3559

    Article  CAS  PubMed  Google Scholar 

  6. Hay M et al (2014) Clinical development success rates for investigational drugs. Nat Biotechnol 32(1):40–51

    Article  CAS  PubMed  Google Scholar 

  7. Roth RA, Ganey PE (2010) Intrinsic versus idiosyncratic drug-induced hepatotoxicity–two villains or one? J Pharmacol Exp Ther 332(3):692–697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Copple IM et al (2010) The keap1-nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug-induced toxicity. Handb Exp Pharmacol 196:233–266

    Article  CAS  PubMed  Google Scholar 

  9. Simmons SO, Fan CY, Ramabhadran R (2009) Cellular stress response pathway system as a sentinel ensemble in toxicological screening. Toxicol Sci 111(2):202–225

    Article  CAS  PubMed  Google Scholar 

  10. Srivastava A et al (2010) Role of reactive metabolites in drug-induced hepatotoxicity. Handb Exp Pharmacol 196:165–194

    Article  CAS  PubMed  Google Scholar 

  11. Bryan HK et al (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 85(6):705–717

    Article  CAS  PubMed  Google Scholar 

  12. Osburn WO, Kensler TW (2008) Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res 659(1–2):31–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 34(6):340–346

    Article  CAS  PubMed  Google Scholar 

  14. Valko M et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84

    Article  CAS  PubMed  Google Scholar 

  15. Chan K, Han XD, Kan YW (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A 98(8):4611–4616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Rangasamy T et al (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114(9):1248–1259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Umemura T et al (2006) A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol. Toxicol Sci 90(1):111–119

    Article  CAS  PubMed  Google Scholar 

  18. Cho HY et al (2004) The transcription factor NRF2 protects against pulmonary fibrosis. Faseb J 18(11):1258–1260

    CAS  PubMed  Google Scholar 

  19. Kultz D (2005) Molecular and evolutionary basis of the cellular stress response. Annu Rev Physiol 67:225–257

    Article  PubMed  Google Scholar 

  20. Itoh K et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236(2):313–322

    Article  CAS  PubMed  Google Scholar 

  21. Chan JY, Kwong M (2000) Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim Biophys Acta 1517(1):19–26

    Article  CAS  PubMed  Google Scholar 

  22. Kwak MK et al (2001) Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 7(2):135–145

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Ramos-Gomez M et al (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A 98(6):3410–3415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Enomoto A et al (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59(1):169–177

    Article  CAS  PubMed  Google Scholar 

  25. Okawa H et al (2006) Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun 339(1):79–88

    Article  CAS  PubMed  Google Scholar 

  26. Takaya K et al (2012) Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic Biol Med 53(4):817–827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Fox RJ et al (2013) BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin 30(2):251–262

    Google Scholar 

  28. Jung CH et al (2010) Identification of novel non-coding RNAs using profiles of short sequence reads from next generation sequencing data. BMC Genomics 11:77

    Article  PubMed Central  PubMed  Google Scholar 

  29. Vacchi-Suzzi C et al (2012) Perturbation of microRNAs in rat heart during chronic doxorubicin treatment. PLoS One 7(7), e40395

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Wang K et al (2009) Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 106(11):4402–4407

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Nuwaysir EF et al (1999) Microarrays and toxicology: the advent of toxicogenomics. Mol Carcinog 24(3):153–159

    Article  CAS  PubMed  Google Scholar 

  32. Aardema MJ, MacGregor JT (2002) Toxicology and genetic toxicology in the new era of “toxicogenomics”: impact of “-omics” technologies. Mutat Res 499(1):13–25

    Article  CAS  PubMed  Google Scholar 

  33. Hamadeh HK et al (2002) Gene expression analysis reveals chemical-specific profiles. Toxicol Sci 67(2):219–231

    Article  CAS  PubMed  Google Scholar 

  34. Heinloth AN et al (2004) Gene expression profiling of rat livers reveals indicators of potential adverse effects. Toxicol Sci 80(1):193–202

    Article  CAS  PubMed  Google Scholar 

  35. Powell CL et al (2006) Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. Toxicol Sci 93(1):213–222

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Goldring CE et al (2004) Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 39(5):1267–1276

    Article  CAS  PubMed  Google Scholar 

  37. McMillian M et al (2005) Drug-induced oxidative stress in rat liver from a toxicogenomics perspective. Toxicol Appl Pharmacol 207(2 Suppl):171–178

    Article  PubMed  Google Scholar 

  38. McMillian M et al (2004) A gene expression signature for oxidant stress/reactive metabolites in rat liver. Biochem Pharmacol 68(11):2249–2261

    Article  CAS  PubMed  Google Scholar 

  39. McMillian M et al (2004) Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver. Biochem Pharmacol 67(11):2141–2165

    Article  CAS  PubMed  Google Scholar 

  40. Kwak MK et al (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278(10):8135–8145

    Article  CAS  PubMed  Google Scholar 

  41. Deferme L et al (2013) Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology 306:24–34

    Article  CAS  PubMed  Google Scholar 

  42. National Research Council (U.S.). Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology (2007) Applications of toxicogenomic technologies to predictive toxicology and risk assessment. Washington, DC

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Discovery Toxicology, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA, 91320, USA

    Christine M. Karbowski, Melissa M. Martin & Paul Nioi

Authors
  1. Christine M. Karbowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melissa M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Nioi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christine M. Karbowski .

Editor information

Editors and Affiliations

  1. Center for Environmental & Human Toxicology, University of Florida, Gainesville, Florida, USA

    Stephen M. Roberts

  2. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

    James P. Kehrer

  3. Department of Nutrigenomics, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Thüringen, Germany

    Lars-Oliver Klotz

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Karbowski, C.M., Martin, M.M., Nioi, P. (2015). Toxicogenomics-Based Assessment of Xenobiotic-Induced Oxidative Stress. In: Roberts, S., Kehrer, J., Klotz, LO. (eds) Studies on Experimental Toxicology and Pharmacology. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-19096-9_25

Download citation

Publish with us

Policies and ethics

Search

Navigation