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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

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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

dc.contributor.author	Godoy, Patricio	es_ES
dc.contributor.author	Hewitt, Nicola J.	es_ES
dc.contributor.author	Albrecht, Ute	es_ES
dc.contributor.author	Andersen, Melvin E.	es_ES
dc.contributor.author	Ansari, Nariman	es_ES
dc.contributor.author	Bhattacharya, Sudin	es_ES
dc.contributor.author	Bode, Johannes Georg	es_ES
dc.contributor.author	Bolleyn, Jennifer	es_ES
dc.contributor.author	Borner, Christoph	es_ES
dc.contributor.author	Böttger, Jan	es_ES
dc.contributor.author	Braeuning, Albert	es_ES
dc.contributor.author	Budinsky, Robert A.	es_ES
dc.contributor.author	Burkhardt, Britta	es_ES
dc.contributor.author	Cameron, Neil R.	es_ES
dc.contributor.author	Camussi, Giovanni	es_ES
dc.contributor.author	Cho, Chong-Su	es_ES
dc.contributor.author	Choi, Yun-Jaie	es_ES
dc.contributor.author	Craig Rowlands, J.	es_ES
dc.contributor.author	Dahmen, Uta	es_ES
dc.contributor.author	Damm, Georg	es_ES
dc.contributor.author	Dirsch, Olaf	es_ES
dc.contributor.author	Donato Martín, María Teresa	es_ES
dc.contributor.author	Dong, Jian	es_ES
dc.contributor.author	Dooley, Steven	es_ES
dc.contributor.author	Drasdo, Dirk	es_ES
dc.contributor.author	Eakins, Rowena	es_ES
dc.contributor.author	Ferreira, Karine Sá	es_ES
dc.contributor.author	Fonsato, Valentina	es_ES
dc.contributor.author	Fraczek, Joanna	es_ES
dc.contributor.author	Gebhardt, Rolf	es_ES
dc.contributor.author	Gibson, Andrew	es_ES
dc.contributor.author	Glanemann, Matthias	es_ES
dc.contributor.author	Goldring, Chris E. P.	es_ES
dc.contributor.author	Gómez-Lechón Moliner, Mª José	es_ES
dc.contributor.author	Groothuis, Geny M. M.	es_ES
dc.contributor.author	Gustavsson, Lena	es_ES
dc.contributor.author	Guyot, Christelle	es_ES
dc.contributor.author	Hallifax, David	es_ES
dc.contributor.author	Hammad, Seddik	es_ES
dc.contributor.author	Hayward, Adam	es_ES
dc.contributor.author	Häussinger, Dieter	es_ES
dc.contributor.author	Hellerbrand, Claus	es_ES
dc.contributor.author	Hewitt, Philip	es_ES
dc.contributor.author	Hoehme, Stefan	es_ES
dc.contributor.author	Holzhütter, Hermann-Georg	es_ES
dc.contributor.author	Houston, J. Brian	es_ES
dc.contributor.author	Hrach, Jens	es_ES
dc.contributor.author	Ito, Kiyomi	es_ES
dc.contributor.author	Jaeschke, Hartmut	es_ES
dc.contributor.author	Keitel, Verena	es_ES
dc.contributor.author	Kelm, Jens M.	es_ES
dc.contributor.author	Kevin Park, B.	es_ES
dc.contributor.author	Kordes, Claus	es_ES
dc.contributor.author	Kullak-Ublick, Gerd A.	es_ES
dc.contributor.author	LeCluyse, Edward L.	es_ES
dc.contributor.author	Lu, Peng	es_ES
dc.contributor.author	Luebke-Wheeler, Jennifer	es_ES
dc.contributor.author	Lutz, Anna	es_ES
dc.contributor.author	Maltman, Daniel J.	es_ES
dc.contributor.author	Matz-Soja, Madlen	es_ES
dc.contributor.author	McMullen, Patrick	es_ES
dc.contributor.author	Merfort, Irmgard	es_ES
dc.contributor.author	Messner, Simon	es_ES
dc.contributor.author	Meyer, Christoph	es_ES
dc.contributor.author	Mwinyi, Jessica	es_ES
dc.contributor.author	Naisbitt, Dean J.	es_ES
dc.contributor.author	Nussler, Andreas K.	es_ES
dc.contributor.author	Olinga, Peter	es_ES
dc.contributor.author	Pampaloni, Francesco	es_ES
dc.contributor.author	Pi, Jingbo	es_ES
dc.contributor.author	Pluta, Linda	es_ES
dc.contributor.author	Przyborski, Stefan A.	es_ES
dc.contributor.author	Ramachandran, Anup	es_ES
dc.contributor.author	Rogiers, Vera	es_ES
dc.contributor.author	Rowe, Cliff	es_ES
dc.contributor.author	Schelcher, Celine	es_ES
dc.contributor.author	Schmich, Kathrin	es_ES
dc.contributor.author	Schwarz, Michael	es_ES
dc.contributor.author	Singh, Bijay	es_ES
dc.contributor.author	Stelzer, Ernst H. K.	es_ES
dc.contributor.author	Stieger, Bruno	es_ES
dc.contributor.author	Stöber, Regina	es_ES
dc.contributor.author	Sugiyama, Yuichi	es_ES
dc.contributor.author	Tetta, Ciro	es_ES
dc.contributor.author	Thasler, Wolfgang E.	es_ES
dc.contributor.author	Vanhaecke, Tamara	es_ES
dc.contributor.author	Vinken, Mathieu	es_ES
dc.contributor.author	Weiss, Thomas S.	es_ES
dc.contributor.author	Widera, Agata	es_ES
dc.contributor.author	Woods, Courtney G.	es_ES
dc.contributor.author	Xu, Jinghai James	es_ES
dc.contributor.author	Yarborough, Kathy M.	es_ES
dc.contributor.author	Hengstler, Jan G.	es_ES
dc.date.accessioned	2015-06-18T12:29:21Z
dc.date.available	2015-06-18T12:29:21Z
dc.date.issued	2013	es_ES
dc.identifier.citation	Archives of Toxicology Vol. 87 Issue 8: pp. 1315-1530	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44475
dc.description.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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.	es_ES
dc.subject	Non-parenchymal cells	es_ES
dc.subject	Mechanisms of gene regulation	es_ES
dc.subject	DILI	es_ES
dc.subject	3D Models	es_ES
dc.subject	Cryopreservation	es_ES
dc.subject	Clearance	es_ES
dc.subject	Mathematical modeling	es_ES
dc.title	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	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1007/s00204-013-1078-5	es_ES
dc.identifier.idgrec	090874	es_ES