From Drug Identification to Systems Toxicology

  • Donata Favretto


Biomedical sciences are at the edge of an extraordinary transformation in the conduct of toxicological evaluations using modern biomolecular analysis techniques to elucidate mechanisms of toxicity. To this transformation have contributed the increasing power and availability of molecular measurement tools, the possibility of probing biological networks inside organisms, organs, tissues, and cells, the affordability of high-throughput characterization tools, and the availability of potent bioinformatic tools. The classical toxicant-by-toxicant approach, that has been applied to solve clinical and forensic toxicology challenges for decades, has now turned to a multidisciplinary approach. The application of the newest biomolecular measurements to the field of toxicology led to the emergence of new sub-disciplines, such as toxicogenetics, toxicoproteomics, and systems toxicology. The leading approaches are briefly reviewed, with a special focus on technological advances, the omics era, systems toxicology and the toxome.


  1. 1.
    Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5:936–948CrossRefPubMedGoogle Scholar
  2. 2.
    Amala S (2010) Toxicogenomics. J Bioinform Seq Anal 2(4):42–46Google Scholar
  3. 3.
    Chen M, Zhang M, Borlak J, Tong W (2012) A decade of toxicogenomic research and its contribution to toxicological science. Toxicol Sci 130(2):217–228CrossRefPubMedGoogle Scholar
  4. 4.
    Norris JL, Caprioli RM (2013) Imaging mass spectrometry: a new tool for pathology in a molecular age. Proteomics Clin Appl 7:733–738CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Deutskens F, Yang J, Caprioli RM (2011) High spatial resolution imaging mass spectrometry and classical histology on a single tissue section. J Mass Spectrom 46(6):568–571CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT (1997) Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles. Clin Chem 43(7):1129–1141PubMedGoogle Scholar
  7. 7.
    Sauer S, Kliem M (2010) Mass spectrometry tools for the classification and identification of bacteria. Nat Rev Microbiol 8(1):74–82. doi: 10.1038/nrmicro2243CrossRefPubMedGoogle Scholar
  8. 8.
    Meng QH (2013) Mass spectrometry applications in clinical diagnostics. J Clin Exp Pathol, S6Google Scholar
  9. 9.
    Andresen H, Augustin C, Streichert T (2013) Toxicogenetics–cytochrome P450 microarray analysis in forensic cases focusing on morphine/codeine and diazepam. Int J Legal Med 127(2):395–404CrossRefPubMedGoogle Scholar
  10. 10.
    Wang Y, Jurgen B, Weida T (2013) Toxicogenomics–a drug development perspective. In: Yao Y, Jallal B, Ranade K (eds) Genomic biomarkers for pharmaceutical development. Elsevier Inc, Amsterdam, pp 127–155Google Scholar
  11. 11.
    Kerksick Chad M et al (2015) How can bioinformatics and toxicogenomics assist the next generation of research on physical exercise and athletic performance. J Strength Conditioning Res 29:270–278CrossRefGoogle Scholar
  12. 12.
    Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929CrossRefPubMedGoogle Scholar
  13. 13.
    Levo A, Koski A, Ojanperä I, Vuori E, Sajantila A (2003) Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic Sci Int 135:9–15CrossRefPubMedGoogle Scholar
  14. 14.
    Madadi P, Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder JS, Teitelbaum R, Karaskov T, Aleksa K (2007) Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 53:33–35PubMedPubMedCentralGoogle Scholar
  15. 15.
    Musshoff F, Stamer UM, Madea B (2010) Pharmacogenetics and forensic toxicology. Forensic Sci Int 203(1–3):53–62CrossRefPubMedGoogle Scholar
  16. 16.
    Morris MK, Chi A, Melas IN, Alexopoulos LG (2014) Phosphoproteomics in drug discovery. Drug Discov Today 19:425–432CrossRefPubMedGoogle Scholar
  17. 17.
    Bausch-Fluck D, Hofmann A, Wollscheid B (2012) Cell surface capturing technologies for the surfaceome discovery of hepatocytes. Methods Mol Biol 909:1–16PubMedGoogle Scholar
  18. 18.
    Deininger L, Patel E, Clench MR, Sears V, Sammon C, Francese S (2016) Proteomics goes forensic: detection and mapping of blood signatures in fingermarks. Proteomics 16(11–12):1707–1717CrossRefPubMedGoogle Scholar
  19. 19.
    Merrick BA, Witzmann FA (2009) The role of toxicoproteomics in assessing organ specific toxicity. EXS 99:367–400PubMedPubMedCentralGoogle Scholar
  20. 20.
    George J, Singh R, Mahmood Z, Shukla Y (2010) Toxicoproteomics: new paradigms in toxicology research. Toxicol Mech Methods 20(7):415–423CrossRefPubMedGoogle Scholar
  21. 21.
    Nagana Gowda GA, Raftery D (2013) biomarker discovery and translation in metabolomics. Curr Metabolomics 1(3):227–240CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fiehn O (2001) Combining genomics, metabolome analysis, and biochemical modeling to understand metabolic networks. Comp Funct Genomics 2:155–168CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Athersuch TJ (2012) The role of metabolomics in characterizing the human exposome. Bioanalysis 4(18):2207–2212CrossRefPubMedGoogle Scholar
  24. 24.
    Rappaport SM (2012) Biomarkers intersect with the exposome. Biomarkers 17(6):483–489CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85(2):809–822CrossRefPubMedGoogle Scholar
  26. 26.
    Bouhifd M, Hartung T, Hogberg HT, Kleensang A, Zhao L (2013) Review: toxicometabolomics. J Appl Toxicol 33(12):1365–1383CrossRefPubMedGoogle Scholar
  27. 27.
    Ramirez T, Daneshian M, Kamp H et al (2013) Metabolomics in toxicology and preclinical research. Altex 30(2):209–225CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rappaport SM, Li H, Grigoryan H, Funk WE, Williams ER (2012) Adductomics: characterizing exposures to reactive electrophiles. Toxicol Lett 213(1):83–90CrossRefPubMedGoogle Scholar
  29. 29.
    Pan Z, Raftery D (2007) Comparing and combining NMR spectroscopy and mass spectrometry in metabolomics. Anal Bioanal Chem 387:525–527CrossRefPubMedGoogle Scholar
  30. 30.
    Dunn WB, Broadhurst DI, Atherton HJ, Goodacre R, Griffin JL (2011) Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chem Soc Rev 40(1):387–426CrossRefPubMedGoogle Scholar
  31. 31.
    Robertson DG, Watkins PB, Reily MD (2011) Metabolomics in toxicology: preclinical and clinical applications. Toxicol Sci 120(Suppl 1):S146–S470CrossRefPubMedGoogle Scholar
  32. 32.
    Castillo-Peinado LS, Luque de Castro MD (2016) Present and foreseeable future of metabolomics in forensic analysis. Anal Chim Acta 925:1–15CrossRefPubMedGoogle Scholar
  33. 33.
    Shipkova D, Reily M (2010) PLC–MS in endogenous metabolite profiling and small-molecule biomarker discovery. In: Lee MS, Zhu M (eds) Mass spectrometry in drug metabolism and disposition: basic principles and applications. Wiley, Blackwell, Oxford, pp 685–722Google Scholar
  34. 34.
    Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66CrossRefPubMedGoogle Scholar
  35. 35.
    Drasdo D, Hoehme S, Hengstler JG (2014) How predictive quantitative modelling of tissue organisation can inform liver disease pathogenesis. J Hepatol 61:951–956CrossRefPubMedGoogle Scholar
  36. 36.
    Drasdo D, Bode J, Dahmen U, Dirsch O, Dooley S, Gebhardt R, Ghallab A, Godoy P, Häussinger D, Hammad S, Hoehme S, Holzhütter HG, Klingmüller U, Kuepfer L, Timmer J, Zerial M, Hengstler JG (2014) The virtual liver: state of the art and future perspectives. Arch Toxicol 88:2071–2075CrossRefPubMedGoogle Scholar
  37. 37.
    Hoehme S, Brulport M, Bauer A et al (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A 107:10371–10376CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S (2014) Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505:97–102CrossRefPubMedGoogle Scholar
  39. 39.
    Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468:310–315CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Madea B, Saukko P, Oliva A, Musshoff F (2010) Molecular pathology in forensic medicine–Introduction. Forensic Sci Int 203(1–3):3–14CrossRefPubMedGoogle Scholar
  41. 41.
    Bouhifd M, Andersen ME, Baghdikian C, Boekelheide K, Crofton KM, Fornace AJ Jr, Kleensang A, Li H, Livi C, Maertens A, McMullen PD, Rosenberg M, Thomas R, Vantangoli M, Yager JD, Zhao L, Hartung T (2015) The human toxome project. Altex 32:112–124CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nebert DW, Ingelman-Sundberg M (2016) What do animal experiments tell us that in vitro systems cannot? The Human Toxome Project. Regul Toxicol Pharmacol 75:1–4CrossRefPubMedGoogle Scholar
  43. 43.
    Juberg DR, Borghoff SJ, Becker RA et al (2014) t4 workshop report–lessons learned, challenges, and opportunities: the U.S. Endocrine Disruptor Screening Program. ALTEX 31:63–78CrossRefPubMedGoogle Scholar
  44. 44.
    Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO (1995) The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect 103(Suppl 7):113–122CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Acevedo N, Davis B, Schaeberle CM, Sonnenschein C, Soto AM (2013) Perinatally administered bisphenol a as a potential mammary gland carcinogen in rats. Environ Health Perspect 121:1040–1046PubMedPubMedCentralGoogle Scholar
  46. 46.
    Miller S, Kennedy D, Thomson J, Han F, Smith R, Ing N, Piedrahita J, Busbee D (2000) A rapid and sensitive reporter gene that uses green fluorescent protein expression to detect chemicals with estrogenic activity. Toxicol Sci 55:69–77CrossRefPubMedGoogle Scholar
  47. 47.
    Bovee TF, Helsdingen RJ, Koks PD, Kuiper HA, Hoogenboom RL, Keijer J (2004) Development of a rapid yeast estrogen bioassay, based on the expression of green fluorescent protein. Gene 325:187–200CrossRefPubMedGoogle Scholar
  48. 48.
    Huan J, Wang L, Xing L, Qin X, Feng L, Pan X, Zhu L (2014) Insights into significant pathways and gene interaction networks underlying breast cancer cell line MCF-7 treated with 17β-estradiol (E2). Gene 533:346–355CrossRefPubMedGoogle Scholar
  49. 49.
    Kolle SN, Ramirez T, Kamp HG, Buesen R, Flick B, Strauss V, van Ravenzwaay B (2012) A testing strategy for the identification of mammalian, systemic endocrine disruptors with particular focus on steroids. Regul Toxicol Pharmacol 63:259–278CrossRefPubMedGoogle Scholar
  50. 50.
    Notas G, Kampa M, Pelekanou V, Castanas E (2012) Interplay of estrogen receptors and GPR30 for the regulation of early membrane initiated transcriptional effects: a pharmacological approach. Steroids 77:943–950CrossRefPubMedGoogle Scholar
  51. 51.
    Hartung T, McBride M (2011) Food for Thought … on mapping the human toxome. Altex 28(2):83–93CrossRefPubMedGoogle Scholar
  52. 52.
    Bouhifd M, Hogberg HT, Kleensang A, Maertens A, Zhao L, Hartung T (2014) Mapping the human toxome by systems toxicology. Basic Clin Pharmacol Toxicol 115(1):24–31CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Richard AM (2006) Future of toxicology–predictive toxicology: An expanded view of “chemical toxicity”. Chem Res Toxicol 19(10):1257–1262CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Legal and Occupational Medicine, Toxicology and Public HealthUniversity-Hospital of PaduaPaduaItaly

Personalised recommendations