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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, Patricio (author)
Hewitt, Nicola J. (author)
Albrecht, Ute (author)
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Andersen, Melvin E. (author)
Ansari, Nariman (author)
Bhattacharya, Sudin (author)
Bode, Johannes Georg (author)
Bolleyn, Jennifer (author)
Borner, Christoph (author)
Boettger, Jan (author)
Braeuning, Albert (author)
Budinsky, Robert A. (author)
Burkhardt, Britta (author)
Cameron, Neil R. (author)
Camussi, Giovanni (author)
Cho, Chong-Su (author)
Choi, Yun-Jaie (author)
Rowlands, J. Craig (author)
Dahmen, Uta (author)
Damm, Georg (author)
Dirsch, Olaf (author)
Teresa Donato, Maria (author)
Dong, Jian (author)
Dooley, Steven (author)
Drasdo, Dirk (author)
Eakins, Rowena (author)
Ferreira, Karine Sa (author)
Fonsato, Valentina (author)
Fraczek, Joanna (author)
Gebhardt, Rolf (author)
Gibson, Andrew (author)
Glanemann, Matthias (author)
Goldring, Chris E. P. (author)
Jose Gomez-Lechon, Maria (author)
Groothuis, Geny M. M. (author)
Gustavsson, Lena (author)
Lund University,Lunds universitet,Institutionen för translationell medicin,Medicinska fakulteten,Department of Translational Medicine,Faculty of Medicine
Guyot, Christelle (author)
Hallifax, David (author)
Hammad, Seddik (author)
Hayward, Adam (author)
Haeussinger, Dieter (author)
Hellerbrand, Claus (author)
Hewitt, Philip (author)
Hoehme, Stefan (author)
Holzhuetter, Hermann-Georg (author)
Houston, J. Brian (author)
Hrach, Jens (author)
Ito, Kiyomi (author)
Jaeschke, Hartmut (author)
Keitel, Verena (author)
Kelm, Jens M. (author)
Park, B. Kevin (author)
Kordes, Claus (author)
Kullak-Ublick, Gerd A. (author)
LeCluyse, Edward L. (author)
Lu, Peng (author)
Luebke-Wheeler, Jennifer (author)
Lutz, Anna (author)
Maltman, Daniel J. (author)
Matz-Soja, Madlen (author)
McMullen, Patrick (author)
Merfort, Irmgard (author)
Messner, Simon (author)
Meyer, Christoph (author)
Mwinyi, Jessica (author)
Naisbitt, Dean J. (author)
Nussler, Andreas K. (author)
Olinga, Peter (author)
Pampaloni, Francesco (author)
Pi, Jingbo (author)
Pluta, Linda (author)
Przyborski, Stefan A. (author)
Ramachandran, Anup (author)
Rogiers, Vera (author)
Rowe, Cliff (author)
Schelcher, Celine (author)
Schmich, Kathrin (author)
Schwarz, Michael (author)
Singh, Bijay (author)
Stelzer, Ernst H. K. (author)
Stieger, Bruno (author)
Stoeber, Regina (author)
Sugiyama, Yuichi (author)
Tetta, Ciro (author)
Thasler, Wolfgang E. (author)
Vanhaecke, Tamara (author)
Vinken, Mathieu (author)
Weiss, Thomas S. (author)
Widera, Agata (author)
Woods, Courtney G. (author)
Xu, Jinghai James (author)
Yarborough, Kathy M. (author)
Hengstler, Jan G. (author)
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 (creator_code:org_t)
2013-08-23
2013
English.
In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
  • Research review (peer-reviewed)
Abstract Subject headings
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  • 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 alpha, 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 alpha), 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Keyword

Non-parenchymal cells
Mechanisms of gene regulation
DILI
3D Models
Cryopreservation
Clearance
Mathematical modeling

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By the author/editor
Godoy, Patricio
Hewitt, Nicola J ...
Albrecht, Ute
Andersen, Melvin ...
Ansari, Nariman
Bhattacharya, Su ...
show more...
Bode, Johannes G ...
Bolleyn, Jennife ...
Borner, Christop ...
Boettger, Jan
Braeuning, Alber ...
Budinsky, Robert ...
Burkhardt, Britt ...
Cameron, Neil R.
Camussi, Giovann ...
Cho, Chong-Su
Choi, Yun-Jaie
Rowlands, J. Cra ...
Dahmen, Uta
Damm, Georg
Dirsch, Olaf
Teresa Donato, M ...
Dong, Jian
Dooley, Steven
Drasdo, Dirk
Eakins, Rowena
Ferreira, Karine ...
Fonsato, Valenti ...
Fraczek, Joanna
Gebhardt, Rolf
Gibson, Andrew
Glanemann, Matth ...
Goldring, Chris ...
Jose Gomez-Lecho ...
Groothuis, Geny ...
Gustavsson, Lena
Guyot, Christell ...
Hallifax, David
Hammad, Seddik
Hayward, Adam
Haeussinger, Die ...
Hellerbrand, Cla ...
Hewitt, Philip
Hoehme, Stefan
Holzhuetter, Her ...
Houston, J. Bria ...
Hrach, Jens
Ito, Kiyomi
Jaeschke, Hartmu ...
Keitel, Verena
Kelm, Jens M.
Park, B. Kevin
Kordes, Claus
Kullak-Ublick, G ...
LeCluyse, Edward ...
Lu, Peng
Luebke-Wheeler, ...
Lutz, Anna
Maltman, Daniel ...
Matz-Soja, Madle ...
McMullen, Patric ...
Merfort, Irmgard
Messner, Simon
Meyer, Christoph
Mwinyi, Jessica
Naisbitt, Dean J ...
Nussler, Andreas ...
Olinga, Peter
Pampaloni, Franc ...
Pi, Jingbo
Pluta, Linda
Przyborski, Stef ...
Ramachandran, An ...
Rogiers, Vera
Rowe, Cliff
Schelcher, Celin ...
Schmich, Kathrin
Schwarz, Michael
Singh, Bijay
Stelzer, Ernst H ...
Stieger, Bruno
Stoeber, Regina
Sugiyama, Yuichi
Tetta, Ciro
Thasler, Wolfgan ...
Vanhaecke, Tamar ...
Vinken, Mathieu
Weiss, Thomas S.
Widera, Agata
Woods, Courtney ...
Xu, Jinghai Jame ...
Yarborough, Kath ...
Hengstler, Jan G ...
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About the subject
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Basic Medicine
and Pharmacology and ...
Articles in the publication
Archives of Toxi ...
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Lund University

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