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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 1 Nicola J Hewitt 2 Ute Albrecht 3 Melvin E Andersen 4 Nariman Ansari 5 Sudin Bhattacharya 4 Johannes Georg Bode 3 Jennifer Bolleyn 6 Christoph Borner 7 Jan Böttger 8 Albert Braeuning 9 Robert A Budinsky 10 Britta Burkhardt 11 Neil R Cameron 12 Giovanni Camussi 13 Chong-Su Cho 14 Yun-Jaie Choi 14 J. Craig Rowlands 10 Uta Dahmen 15 Georg Damm 16 Olaf Dirsch 17 María Teresa Donato 18 Jian Dong 4 Steven Dooley 19 Dirk Drasdo 20 Rowena Eakins 21 Karine Sá Ferreira 7 Valentina Fonsato 13 Joanna Fraczek 6 Rolf Gebhardt 8 Andrew Gibson 21 Matthias Glanemann 16 Chris E P Goldring 21 María José Gómez-Lechón 22 Geny M M Groothuis 23 Lena Gustavsson 24 Christelle Guyot 25 David Hallifax 26 Seddik Hammad 27 Adam Hayward 28 Dieter Häussinger 3 Claus Hellerbrand 29 Philip Hewitt 30 Stefan Hoehme 8 Hermann-Georg Holzhütter 16 J Brian Houston 26 Jens Hrach 31 Kiyomi Ito 32 Hartmut Jaeschke 33 Verena Keitel 3 Jens M Kelm 34 B. Kevin Park 21 Claus Kordes 3 Gerd A Kullak-Ublick 25 Edward L Lecluyse 4 Peng Lu 4 Jennifer Luebke-Wheeler 35 Anna Lutz 7 Daniel J Maltman 36 Madlen Matz-Soja 37 Patrick Mcmullen 4 Irmgard Merfort 38 Simon Messner 34 Christoph Meyer 19 Jessica Mwinyi 25 Dean J Naisbitt 21 Andreas K Nussler 11 Peter Olinga 23 Francesco Pampaloni 5 Jingbo Pi 4 Linda Pluta 4 Stefan A Przyborski 36 Anup Ramachandran 33 Vera Rogiers 6 Cliff Rowe 21 Celine Schelcher 39 Kathrin Schmich 38 Michael Schwarz 9 Bijay Singh 14 Ernst H K Stelzer 5 Bruno Stieger 25 Regina Stöber 1 Yuichi Sugiyama 40 Ciro Tetta 41 Wolfgang E Thasler 42 Tamara Vanhaecke 6 Mathieu Vinken 6 Thomas S Weiss 29 Agata Widera 1 Courtney G Woods 4 Jinghai James Xu 43 Kathy M Yarborough 4 Jan G Hengstler 1 
20 BANG - Nonlinear Analysis for Biology and Geophysical flows
LJLL - Laboratoire Jacques-Louis Lions, Inria Paris-Rocquencourt
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-4α, 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-4α), 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.
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Submitted on : Wednesday, January 29, 2014 - 8:50:33 PM
Last modification on : Tuesday, July 5, 2022 - 8:38:57 AM

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Patricio Godoy, Nicola J Hewitt, Ute Albrecht, Melvin E Andersen, Nariman Ansari, et al.. 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.. Archives of Toxicology, Springer Verlag, 2013, 87 (8), pp.1315-530. ⟨10.1007/s00204-013-1078-5⟩. ⟨hal-00939009⟩



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