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.
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.
authors: Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139, Dortmund, Germany.
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authors: Hewitt
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authors: Albrecht
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authors: Andersen
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authors: Ansari
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authors: Hewitt
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authors: GA
authors: Kullak-Ublick
authors: Edward L
authors: EL
authors: LeCluyse
authors: Peng
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authors: Lu
authors: Jennifer
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authors: Luebke-Wheeler
authors: Anna
authors: A
authors: Lutz
authors: Daniel J
authors: DJ
authors: Maltman
authors: Madlen
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authors: Matz-Soja
authors: Patrick
authors: P
authors: McMullen
authors: Irmgard
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authors: Merfort
authors: Simon
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authors: Messner
authors: Christoph
authors: C
authors: Meyer
authors: Jessica
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authors: Mwinyi
authors: Dean J
authors: DJ
authors: Naisbitt
authors: Andreas K
authors: AK
authors: Nussler
authors: Peter
authors: P
authors: Olinga
authors: Francesco
authors: F
authors: Pampaloni
authors: Jingbo
authors: J
authors: Pi
authors: Linda
authors: L
authors: Pluta
authors: Stefan A
authors: SA
authors: Przyborski
authors: Anup
authors: A
authors: Ramachandran
authors: Vera
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authors: Rogiers
authors: Cliff
authors: C
authors: Rowe
authors: Celine
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authors: Schelcher
authors: Kathrin
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authors: Schmich
authors: Michael
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authors: Schwarz
authors: Bijay
authors: B
authors: Singh
authors: Ernst H K
authors: EH
authors: Stelzer
authors: Bruno
authors: B
authors: Stieger
authors: Regina
authors: R
authors: Stöber
authors: Yuichi
authors: Y
authors: Sugiyama
authors: Ciro
authors: C
authors: Tetta
authors: Wolfgang E
authors: WE
authors: Thasler
authors: Tamara
authors: T
authors: Vanhaecke
authors: Mathieu
authors: M
authors: Vinken
authors: Thomas S
authors: TS
authors: Weiss
authors: Agata
authors: A
authors: Widera
authors: Courtney G
authors: CG
authors: Woods
authors: Jinghai James
authors: JJ
authors: Xu
authors: Kathy M
authors: KM
authors: Yarborough
authors: Jan G
authors: JG
authors: Hengstler
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D046508:Culture Techniques / Q000379:methods*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear
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