Archives of Toxicology

, Volume 88, Issue 12, pp 2099–2133

SEURAT-1 liver gold reference compounds: a mechanism-based review

  • Paul Jennings
  • Michael Schwarz
  • Brigitte Landesmann
  • Silvia Maggioni
  • Marina Goumenou
  • David Bower
  • Martin O. Leonard
  • Jeffrey S. Wiseman
Review Article

DOI: 10.1007/s00204-014-1410-8

Cite this article as:
Jennings, P., Schwarz, M., Landesmann, B. et al. Arch Toxicol (2014) 88: 2099. doi:10.1007/s00204-014-1410-8

Abstract

There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for ‘Safety Evaluation Ultimately Replacing Animal Testing.’ The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation.

Keywords

SEURAT-1 Hepatotoxin MIE MoA Nuclear receptor Stress response 

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Paul Jennings
    • 1
  • Michael Schwarz
    • 2
  • Brigitte Landesmann
    • 3
  • Silvia Maggioni
    • 4
  • Marina Goumenou
    • 5
  • David Bower
    • 6
  • Martin O. Leonard
    • 7
  • Jeffrey S. Wiseman
    • 8
  1. 1.Division of Physiology, Department of Physiology and Medical PhysicsMedical University of InnsbruckInnsbruckAustria
  2. 2.Institute of Experimental and Clinical Pharmacology and Toxicology, Department of ToxicologyUniversity of TuebingenTuebingenGermany
  3. 3.Systems Toxicology Unit and the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Institute for Health and Consumer Protection, Joint Research CentreEuropean CommissionIspraItaly
  4. 4.Department of Environmental Health SciencesIstituto di Ricerche Farmacologiche Mario NegriMilanItaly
  5. 5.European Food Safety AuthorityParmaItaly
  6. 6.Leadscope, Inc.ColumbusUSA
  7. 7.Centre for Radiation, Chemical and Environmental HazardsPublic Health EnglandDidcotUK
  8. 8.Pharmatrope, Ltd.DowningtownUSA