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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.

Godoy, P. and Hewitt, N.J. and Albrecht, U. and Andersen, M.E. and Ansari, N. and Bhattacharya, S. and Bode, J.G. and Bolleyn, J. and Borner, C. and Böttger, J. and Braeuning, A. and Budinsky, R.A. and Burkhardt, B. and Cameron, N.R. and Camussi, G. and Cho, C.S. and Choi, Y.J. and Craig, Rowlands J. and Dahmen, U. and Damm, G. and Dirsch, O. and Donato, M.T. and Dong, J. and Dooley, S. and Drasdo, D. and Eakins, R. and Ferreira, K.S. and Fonsato, V. and Fraczek, J. and Gebhardt, R. and Gibson, A. and Glanemann, M. and Goldring, C.E. and Gómez-Lechón, M.J. and Groothuis, G.M. and Gustavsson, L. and Guyot, C. and Hallifax, D. and Hammad, S. and Hayward, A. and Häussinger, D. and Hellerbrand, C. and Hewitt, P. and Hoehme, S. and Holzhütter, H.G. and Houston, J.B. and Hrach, J. and Ito, K. and Jaeschke, H. and Keitel, V. and Kelm, J.M. and Kevin Park, B. and Kordes, C. and Kullak-Ublick, G.A. and LeCluyse, E.L. and Lu, P. and Luebke-Wheeler, J. and Lutz, A. and Maltman, D.J. and Matz-Soja, M. and McMullen, P. and Merfort, I. and Messner, S. and Meyer, C. and Mwinyi, J. and Naisbitt, D.J. and Nussler, A.K. and Olinga, P. and Pampaloni, F. and Pi, J. and Pluta, L. and Przyborski, S.A. and Ramachandran, A. and Rogiers, V. and Rowe, C. and Schelcher, C. and Schmich, K. and Schwarz, M. and Singh, B. and Stelzer, E.H. and Stieger, B. and Stöber, R. and Sugiyama, Y. and Tetta, C. and Thasler, W.E. and Vanhaecke, T. and Vinken, M. and Weiss, T.S. and Widera, A. and Woods, C.G. and Xu, J.J. and Yarborough, K.M. and Hengstler, J.G. (2013) '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., 87 (8). pp. 1315-1530.


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.

Item Type:Article
Keywords:Non-parenchymal cells, Mechanisms of gene regulation, DILI, 3D Models, Cryopreservation, Clearance, Mathematical modeling.
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Publisher statement:© The Author(s) 2013. This article is published with open access at Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Date accepted:06 May 2013
Date deposited:08 June 2015
Date of first online publication:August 2013
Date first made open access:No date available

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