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.
Bibliographical noteFunding Information:
Acknowledgments This work was funded by ToxBank (Grant Agreement No. 267042), COACH (Grant Agreement No. 267044), and DETECTIVE (Grant Agreement No. 266838) projects through the EU Seventh Framework Programme HEALTH-2010-4.2.9 Alternative Testing Strategies (Health-F5-2010-267042) and Cosmetics Europe. Compound selection was guided by extensive input from across the SEURAT-1 program, in particular from the ‘Gold Compound Working Group’ that provided input to the strategy and candidate reference standards and the ‘Gold Compound Assessment Team’ that compiled data from the literature to build the ToxBank Wiki (Toxbank) data tables for each compound. We gratefully acknowledge the extensive effort contributed by these teams, without which this effort would not have been possible. Members of the software team who created and maintain the ToxBank Wiki are David Bower, Micah Rautenberg, Egon Willighagen, and Glenn Myatt. Members of the Gold Compound Assessment Team were David Bower, Matthew Clark, Matthew Dent, Marina Goumenou, Gabrielle Hawksworth, Nina Jeliazkova, Brigitte Landesmann, Silvia Maggioni, Andrew White, Jeffrey Wiseman, and Egon Willighagen. Members of the Gold Compound Working Group were Roman Affentranger, Gordana Apic, Emilio Benfenati, Ian Cotgreave, Barry Hardy, Jan Hengstler, Susanne Bremer-Hoffmann, Paul Jennings, Giovanna Lazzari, Inge Mangelsdorf, Filomain Nguemo, Foozia Noor, Agapios Sachinidis, Michael Schwarz, Leo van Grunsven, Mathieu Vinken, Manfred Wat-zele, Jeffrey Wiseman, and Jose-Manuel Zaldivar.
© 2014, Springer-Verlag Berlin Heidelberg.
- Nuclear receptor
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