Journal
ARCHIVES OF TOXICOLOGY
Volume 87, Issue 8, Pages 1315-1530Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-013-1078-5
Keywords
Non-parenchymal cells; Mechanisms of gene regulation; DILI; 3D Models; Cryopreservation; Clearance; Mathematical modeling
Categories
Funding
- BMBF-VIRTUAL-LIVER network
- BMBF
- FP6 program projects, Liintop
- PREDICTOMICS
- carcinoGENOMICS
- EU
- BMBF program Alternatives to animal testing
- ANR
- National Research Foundation of Korea
- Korean Government (MEST) [NRF-2011-0009592]
- Institut d'encouragement de la Recherche Scientifique et de l'Innovation de Bruxelles
- ISRIB, Innoviris (Brustem project)
- Belgian Science Policy (BELSPO) project
- HEPRO
- Geconcerteerde Onderzoek Acties (GOA project)
- Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO)
- Research Council VUB
- National Institutes of Health [AA12916, DK070195]
- Medical Faculty of the University of Regensburg (ReForM-Program)
- German Ministry of Education and Research (BMBF) within the Human Tissue and Cell Research (HTCR) Foundation
- Excellence Initiative of the German Federal and State Governments [GSC-4]
- Spemann Graduate School of Biology and Medicine (SGBM)
- EXC-294, Centre for Biological Signaling Studies (BIOSS)
- GRK 1104-From Cells to Organs: Molecular Mechanisms of Organogenesis from the Deutsche Forschungsgemeinschaft (DFG)
- Swiss National Science [31003A_124652]
- Swiss National Science Foundation (SNF) [31003A_124652] Funding Source: Swiss National Science Foundation (SNF)
- Biotechnology and Biological Sciences Research Council [1233823] Funding Source: researchfish
- Medical Research Council [1092875] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [23590204] Funding Source: KAKEN
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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.
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