6533b85efe1ef96bd12bfe3a
RESEARCH PRODUCT
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.
Kathrin SchmichChristoph MeyerSteven DooleyGerd A. Kullak-ublickDaniel J. MaltmanErnst H. K. StelzerJessica MwinyiValentina FonsatoAlbert BraeuningMelvin E. AndersenMaría José Gómez-lechónGeorg DammPhilip HewittJ. Craig RowlandsJingbo PiLena GustavssonChong Su ChoStefan PrzyborskiThomas S. WeissJoanna FraczekUte AlbrechtRegina StöberBritta BurkhardtAdam S. HaywardSudin BhattacharyaBruno StiegerTamara VanhaeckeCliff RoweKathy YarboroughCeline SchelcherNeil R. CameronAndreas K. NusslerSeddik HammadRowena EakinsOlaf DirschDean J. NaisbittDieter HäussingerRobert A. BudinskyKarine Sá FerreiraChristopher E. GoldringJennifer Luebke-wheelerGiovanni CamussiJ. Brian HoustonJennifer BolleynAndrew GibsonPatrick D. McmullenHermann-georg HolzhütterMichael SchwarzPeng LuJens M. KelmFrancesco PampaloniChristelle GuyotJens HrachUta DahmenJ BöttgerNicola J. HewittBijay SinghVerena KeitelChristoph BornerYuichi SugiyamaAnna LutzEdward L. LecluysePatricio GodoySimon MessnerDirk DrasdoDirk DrasdoDirk DrasdoNariman AnsariCourtney G. WoodsIrmgard MerfortRolf GebhardtMaría Teresa DonatoYun Jaie ChoiClaus KordesB. Kevin ParkJan G. HengstlerJinghai James XuStefan HoehmeClaus HellerbrandPeter OlingaHartmut JaeschkeLinda J. PlutaAgata WideraJohannes G. BodeAnup RamachandranKiyomi ItoMatthias GlanemannDavid HallifaxGeny M. M. GroothuisWolfgang E. ThaslerMathieu VinkenCiro TettaVera RogiersMadlen Matz-sojaJian Dongsubject
MAPK/ERK pathwayHealth Toxicology and MutagenesisNF-KAPPA-BReceptors Cytoplasmic and NuclearReview ArticlePharmacologyToxicologyToxicogeneticsNon-parenchymal cells0302 clinical medicineInduced pluripotent stem cellANION-TRANSPORTING POLYPEPTIDECONSTITUTIVE ANDROSTANE RECEPTOR0303 health sciencesGeneral Medicine3. Good healthCell biologymedicine.anatomical_structureLiver030220 oncology & carcinogenesisHepatocyte[SDV.TOX]Life Sciences [q-bio]/ToxicologyInactivation MetabolicClearanceDILIStem cellPLURIPOTENT STEM-CELLSFARNESOID-X-RECEPTORSignal TransductionMechanisms of gene regulationARYL-HYDROCARBON RECEPTORCell signalingPharmacology and ToxicologyHEPATIC STELLATE CELLSBiology03 medical and health sciencesOrgan Culture TechniquesIn vivoCulture TechniquesToxicity TestsmedicineMathematical modeling.AnimalsHumansLiver X receptorDRUG-DRUG INTERACTIONS030304 developmental biologyCryopreservation[INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation3D ModelsCoculture TechniquesHigh-Throughput Screening AssaysSALT EXPORT PUMPGene Expression RegulationHepatic stellate cellHepatocytes[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/PharmacologyPRIMARY RAT HEPATOCYTESMathematical modelingdescription
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 material The online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-08-01 |