The comparative analysis of in vivo and in vitro transcriptome data based on systems biology


We investigated whether an in vitro cellbased system can represent toxicity of an in vivo organ using gene expression profiles. We performed an analysis of differentially expressed transcripts, pathway analysis, and Gene Ontology (GO) grouping with the toxicity-induced data following treatments with diclofenac, sulindac, itraconazole, and ketoconazole. The number of genes regulated in vitro and in vivo were much more than the randomly sampled number, but no significant correlation was observed between the in vitro and in vivo experiments. We performed a pathway analysis and GO grouping to expand the approach. In the pathway analysis, we narrowed down the hepatotoxic pathways to focus on toxicity. Then, the percentages of overlapping pathways increased. We found pathways associated with liver function in all experiments, such as the adipocyte signaling pathway, JAKSTAT signaling pathway, and peroxisome proliferatoractivated receptor (PPAR) signaling pathway. In the GO grouping analysis, the clusters obtained were primarily related to lipid metabolic and synthetic processes. The percentage of common GO terms between in vitro and in vivo experiments also increased. Therefore, we identified than an analysis performed at the systems biology level was more correlated for in vitro and in vivo systems.

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  1. 1.

    Paul, S.M. et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).

    CAS  Google Scholar 

  2. 2.

    DiMasi, J.A., Hansen, R.W. & Grabowski, H.G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185 (2003).

    Article  Google Scholar 

  3. 3.

    Adams, C.P. & Brantner, V.V. Estimating the cost of new drug development: is it really $802 million? Health Aff. 25, 420–428 (2006).

    Article  Google Scholar 

  4. 4.

    Cohn, M. Alternatives to Animal Testing Gaining Ground. the Baltimore Sun ( 2010).

  5. 5.

    PETA (People for the Ethical Treatment of Animals)

  6. 6.

    BUAV (British Union for the Abolition of Vivisection)

  7. 7.

    Deng, Y.P. et al. In vitro gene regulatory networks predict in vivo function of liver. BMC Syst. Biol. 4, 153 (2010).

    Article  Google Scholar 

  8. 8.

    Bort, R. et al. Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J. Pharmacol. Exp. Ther. 288, 65–72 (1999).

    CAS  Google Scholar 

  9. 9.

    Zou, W. et al. Sulindac metabolism and synergy with tumor necrosis factor-á in a drug-inflammation interaction model of idiosyncratic liver injury. J. Pharmacol. Exp. Ther. 331, 114–121 (2009).

    Article  CAS  Google Scholar 

  10. 10.

    Somchit, N. et al. Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study. Hum. Exp. Toxicol. 23, 519–525 (2004).

    Article  CAS  Google Scholar 

  11. 11.

    Rodriguez, R.J. & Buckholz, C.J. Hepatotoxicity of ketoconazole in Sprague-Dawley rats: glutathione depletion, flavin-containing monooxygenases-mediated bioactivation and hepatic covalent binding. Xenobiotica 33, 429–441 (2003).

    Article  CAS  Google Scholar 

  12. 12.

    Lewis, J.H. NSAID-INDUCED HEPATOTOXICITY. Clin. Liver Dis. 2, 543–561 (1998).

    Article  Google Scholar 

  13. 13.

    DAVID (Database for Annotation, Visualization and Integrated Discovery)

  14. 14.

    Wick, M. et al. Peroxisome proliferator-activated receptor-γ is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. Mol. Pharmacol. 62, 1207–1214 (2002).

    Article  CAS  Google Scholar 

  15. 15.

    Lehmann, J.M. et al. Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 72, 3406–3410 (1997).

    Google Scholar 

  16. 16.

    Göldlin, C.R. & Boelsterli, U.A. Reactive oxygen species and non-peroxidative mechanisms of cocaineinduced cytotoxicity in rat hepatocyte cultures. Toxicology 69, 79–91 (1991).

    Article  Google Scholar 

  17. 17.

    Mayhew, C.N. et al. In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-HIV-1 activity. Stem Cells 17, 345–356 (1999).

    Article  CAS  Google Scholar 

  18. 18.

    Donaldson, K. et al. Concordance between in vitro and in vivo dosimetry in the proinflammatory effects of low-toxicity, low-solubility particles: the key role of the proximal alveolar region. Inhal. Toxicol. 20, 53–62 (2008).

    Article  CAS  Google Scholar 

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Correspondence to YangSeok Kim.

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Jo, Y., Oh, JH., Yoon, S. et al. The comparative analysis of in vivo and in vitro transcriptome data based on systems biology. BioChip J 6, 280–292 (2012).

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  • Comparative analysis
  • Transcriptome data
  • In vitro and in vivo
  • Bioinformatics
  • Systems biology