Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

Patricio Godoy, N. Hewitt, Ute Albrecht, Melvin E. Andersen, Nariman Ansari, Sudin Bhattacharya, Johannes Georg Bode, Jennifer Bolleyn, Christoph Borner, Jan Böttger, Albert Braeuning, Robert A. Budinsky, Britta Burkhardt, Neil R. Cameron, Giovanni Camussi, Chong-Su Cho, Yun-Jaie Choi, Craig Rowlands, Uta Dahmen, Georg DammOlaf Dirsch, Maria Teresa Donato, Jian Dong, Steven Dooley, Dirk Drasdo, Rowena Eakins, Karine Sa Ferreira, Fonsato Valentina, Joanna Fraczek, Rolf Gebhardt, Andrew Gibson, Matthias Glanemann, Chris E.P. Goldring, Maria José Gomez-Lechon, Geny M.M. Groothuis, Lena Gustavsson, Christelle Guyot, David Hallifax, Seddik Hammad, Adam Hayward, Dieter Häussinger, Claus Hellerbrand, Philip Hewitt, Stefan Hoehme, Hermann Georg Holzhütter, J Brian Houston, Jens Hrach, Kiyomi Ito, Hartmut Jaeschke, Verena Keitel, Jens M Kelm, B Kevin Park, Claus Kordes, Gerd A Kullak-Ublick, Edward L Lecluyse, Peng Lu, Jennifer Luebke-Wheeler, Anna Lutz, Daniel J Maltman, Madlen Matz-Soja, Patrick McMullen, Irmgard Merfort, Simon Messner, Meyer Christoph, Jessica Mwinyi, Dean J Naisbitt, Andreas K Nussler, Peter Olinga, Francesco Pampaloni, Jingbo Pi, Linda Pluta, Stefan A Przyborski, Anup Ramachandran, Vera Rogiers, Cliff Rowe, Celine Schelcher, Kathrin Schmich, Michael Schwarz, Bijay Singh, Ernst H.K. Stelzer, Bruno Stieger, Regina Stober, Yuichi Sugiyama, Ciro Tetta, Wolfgang E Thasler, Tamara Vanhaecke, Mathieu Vinken, Thomas S Weiss, Agata Widera, Courtney G Woods, Jinghai James Xu, Kathy M Yarborough, Hengstler Jan

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Abstract

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4?, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4?), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
Original languageEnglish
Pages (from-to)1315-1530
Number of pages216
JournalArchives of Toxicology
Volume87
Publication statusPublished - 23 Aug 2013

Keywords

  • toxicology
  • in vitro methods
  • alternative methods
  • primary hepatocytes
  • safety testing
  • hepatotoxicity
  • epigenetics

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  • Epigen meeting

    Jennifer Bolleyn (Speaker)

    27 Feb 2014

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    Thierry Vandendriessche (Speaker)

    27 Feb 2014

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    Tamara Vanhaecke (Participant)

    27 Feb 2014

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