Impact of cell types and culture methods on the functionality of in vitro liver systems - A review of cell systems for hepatotoxicity assessment.

Xenobiotic safety assessment is an area that impacts a multitude of different industry sectors such as medicinal drugs, agrochemicals, industrial chemicals, cosmetics and environmental contaminants. As such there are a number of well-developed in vitro, in vivo and in silico approaches to evaluate their properties and potential impact on the environment and to humans. Additionally, there is the continual investment in multidisciplinary scientists to explore non-animal surrogate technologies to predict specific toxicological outcomes and to improve our understanding of the biological processes regarding the toxic potential of xenobiotics. Here we provide a concise, critical evaluation of a number of in vitro systems utilised to assess the hepatotoxic potential of xenobiotics.

• Publication year

  2018

• Venue

  Toxicology in Vitro

• Publication date

  2018-02-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1016/j.tiv.2018.01.023PMID 29408671
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Microfluidic Technology for the Generation of Cell Spheroids and Their Applications

  2017cited by this paper
• Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

  2017cited by this paper
• Oxygen tension-independent protection against hypoxic cell killing in rat liver by low sodium

  2017cited by this paper
• Disease Modeling in Stem Cell-Derived 3D Organoid Systems.

  2017cited by this paper
• Decellularized Human Liver Is Too Heterogeneous for Designing a Generic Extracellular Matrix Mimic Hepatic Scaffold

  2017cited by this paper
• A transgenic rat hepatocyte - Kupffer cell co-culture model for evaluation of direct and macrophage-related effect of poly(amidoamine) dendrimers.

  2017cited by this paper
• The Importance of In Vitro Liver Models: Experts Discuss Whole-Cell Systems, Transporter Function, and the Best Models for Future In Vitro Testing

  2016cited by this paper
• Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update

  2016cited by this paper
• 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained

  2016cited by this paper
• Characterization of a functional C3A liver spheroid model

  2016cited by this paper
• Organoids as an in vitro model of human development and disease

  2016cited by this paper
• Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

  2016cited by this paper
• Fluid shear stress modulation of hepatocyte-like cell function

  2016cited by this paper
• Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

  2016cited by this paper
• Three-Dimensional Spheroid Cell Culture Model for Target Identification Utilizing High-Throughput RNAi Screens.

  2016cited by this paper
• In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

  2016cited by this paper
• Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening

  2016cited by this paper
• Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI

  2015cited by this paper
• Poly(vinyl alcohol)/gelatin Hydrogels Cultured with HepG2 Cells as a 3D Model of Hepatocellular Carcinoma: A Morphological Study

  2015cited by this paper
• Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

  2015cited by this paper
• Comparative Proteomic Characterization of 4 Human Liver-Derived Single Cell Culture Models Reveals Significant Variation in the Capacity for Drug Disposition, Bioactivation, and Detoxication

  2015cited by this paper
• Pioneering better science through the 3Rs: an introduction to the national centre for the replacement, refinement, and reduction of animals in research (NC3Rs).

  2015cited by this paper
• Stem Cell-Derived Systems in Toxicology Assessment

  2015cited by this paper
• Hepatic progenitor cells of biliary origin with liver repopulation capacity

  2015cited by this paper
• HepaRG microencapsulated spheroids in DMSO-free culture: novel culturing approaches for enhanced xenobiotic and biosynthetic metabolism

  2015cited by this paper
• Immortalized Human Hepatic Cell Lines for In Vitro Testing and Research Purposes.

  2015cited by this paper
• Modulation of Huh7.5 Spheroid Formation and Functionality Using Modified PEG-Based Hydrogels of Different Stiffness

  2015cited by this paper
• Culture and Functional Characterization of Human Hepatoma HepG2 Cells.

  2015cited by this paper
• Factors affecting drug-induced liver injury: antithyroid drugs as instances

  2014cited by this paper
• In vitro platforms for evaluating liver toxicity

  2014cited by this paper
• Label-free cell phenotypic profiling decodes the composition and signaling of an endogenous ATP-sensitive potassium channel

  2014cited by this paper
• Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation.

  2014cited by this paper
• A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies

  2014cited by this paper
• The application of 3D cell models to support drug safety assessment: opportunities & challenges.

  2014cited by this paper
• Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans.

  2014cited by this paper
• Competency of different cell models to predict human hepatotoxic drugs

  2014cited by this paper
• High-Content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell–Derived Cells

  2014cited by this paper
• A method for estimating the oxygen consumption rate in multicellular tumour spheroids

  2014cited by this paper
• Functional Augmentation of Naturally-Derived Materials for Tissue Regeneration

  2014cited by this paper
• In vitro models for liver toxicity testing.

  2013cited by this paper
• Layered long-term co-culture of hepatocytes and endothelial cells on a transwell membrane: toward engineering the liver sinusoid

  2013cited by this paper
• Vascularized and functional human liver from an iPSC-derived organ bud transplant

  2013cited by this paper
• Galactose-Functionalized PolyHIPE Scaffolds for Use in Routine Three Dimensional Culture of Mammalian Hepatocytes

  2013cited by this paper
• 3D organotypic cultures of human HepaRG cells: a tool for in vitro toxicity studies.

  2013cited by this paper
• A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity.

  2013cited by this paper
• HepG2/C3A 3D spheroids exhibit stable physiological functionality for at least 24 days after recovering from trypsinisation

  2013cited by this paper
• 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

  2013cited by this paper
• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration

  2013cited by this paper
• Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins

  2012cited by this paper
• Organotypic liver culture models: Meeting current challenges in toxicity testing

  2012cited by this paper
• Human liver cell spheroids in extended perfusion bioreactor culture for repeated‐dose drug testing

  2012cited by this paper
• Multi-cell type human liver microtissues for hepatotoxicity testing

  2012cited by this paper
• Comparison of Cryopreserved HepaRG Cells with Cryopreserved Human Hepatocytes for Prediction of Clearance for 26 Drugs

  2012cited by this paper
• Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy.

  2012cited by this paper
• Three-dimensional HepaRG model as an attractive tool for toxicity testing.

  2012cited by this paper
• Novel in vitro and mathematical models for the prediction of chemical toxicity

  2012cited by this paper
• Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity.

  2011cited by this paper
• Pesticide Exposure, Safety Issues, and Risk Assessment Indicators

  2011cited by this paper
• Rat Primary Hepatocytes Show Enhanced Performance and Sensitivity to Acetaminophen During Three-Dimensional Culture on a Polystyrene Scaffold Designed for Routine Use

  2011cited by this paper
• Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes.

  2011cited by this paper
• Alvetex®: polystyrene scaffold technology for routine three dimensional cell culture.

  2011cited by this paper
• HepaRG cells: A human model to study mechanisms of acetaminophen hepatotoxicity

  2011cited by this paper
• Engineering extracellular matrix structure in 3D multiphase tissues.

  2011cited by this paper
• Rapid Generation of In Vitro Multicellular Spheroids for the Study of Monoclonal Antibody Therapy

  2011cited by this paper
• Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2‐specific antagonist is associated with reduced tumor growth

  2011cited by this paper
• Isolation of Primary Human Hepatocytes from Normal and Diseased Liver Tissue: A One Hundred Liver Experience

  2011cited by this paper
• Working in partnership to advance the 3Rs in toxicity testing.

  2010cited by this paper
• Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification.

  2010cited by this paper
• General review on in vitro hepatocyte models and their applications.

  2010cited by this paper
• CYP3A4 Catalytic Activity Is Induced in Confluent Huh7 Hepatoma Cells

  2010cited by this paper
• Mechanisms of acetaminophen-induced liver necrosis.

  2010cited by this paper
• Perfused multiwell plate for 3D liver tissue engineering.

  2010cited by this paper
• Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

  2010cited by this paper
• A Comparison of Whole Genome Gene Expression Profiles of HepaRG Cells and HepG2 Cells to Primary Human Hepatocytes and Human Liver Tissues

  2010cited by this paper
• Hepatospheres: Three dimensional cell cultures resemble physiological conditions of the liver.

  2010cited by this paper
• Co-culture of primary rat hepatocytes with rat liver epithelial cells enhances interleukin-6-induced acute-phase protein response

  2010cited by this paper
• Comparative Analysis of Gene Expression in Rat Liver Tissue and Monolayer- and Spheroid-Cultured Hepatocytes

  2009cited by this paper
• Hemangiosarcoma in rodents: mode-of-action evaluation and human relevance.

  2009cited by this paper
• Inflammatory Pathways in Liver Homeostasis and Liver Injury

  2009cited by this paper
• Hydrogels as extracellular matrix mimics for 3D cell culture.

  2009cited by this paper
• Liver tissue engineering in the evaluation of drug safety

  2009cited by this paper
• Estimates for Worldwide Laboratory Animal Use in 2005: Authors' Response

  2008cited by this paper
• Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism Studies

  2008cited by this paper
• Scaffolding in tissue engineering: general approaches and tissue-specific considerations

  2008cited by this paper
• Monolayer and Spheroid Culture of Human Liver Hepatocellular Carcinoma Cell Line Cells Demonstrate Distinct Global Gene Expression Patterns and Functional Phenotypes

  2008cited by this paper
• Survival advantages of multicellular spheroids vs. monolayers of HepG2 cells in vitro.

  2008cited by this paper
• Nrf2-dependent induction of human ABC transporter ABCG2 and heme oxygenase-1 in HepG2 cells by photoactivation of porphyrins: biochemical implications for cancer cell response to photodynamic therapy.

  2008cited by this paper
• Three-Dimensional Primary Hepatocyte Culture in Synthetic Self-Assembling Peptide Hydrogel

  2008cited by this paper
• Estimates for Worldwide Laboratory Animal Use in 2005

  2008cited by this paper
• The third dimension bridges the gap between cell culture and live tissue

  2007cited by this paper
• Dynamics of the Self-Assembly of Complex Cellular Aggregates on Micromolded Nonadhesive Hydrogels

  2007cited by this paper
• The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics.

  2007cited by this paper
• Oxygen uptake rates and liver‐specific functions of hepatocyte and 3T3 fibroblast co‐cultures

  2007cited by this paper
• Culture of HepG2 liver cells on three dimensional polystyrene scaffolds enhances cell structure and function during toxicological challenge

  2007cited by this paper
• Precision-cut tissue slices as a tool to predict metabolism of novel drugs

  2007cited by this paper
• EXPRESSION OF CYTOCHROMES P450, CONJUGATING ENZYMES AND NUCLEAR RECEPTORS IN HUMAN HEPATOMA HepaRG CELLS

  2006cited by this paper
• Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and β1-integrin

  2006cited by this paper
• Design of Custom-Shaped Vascularized Tissues Using Microtissue Spheroids as Minimal Building Units

  2006cited by this paper
• Hepatocyte and Kupffer Cells Co-cultured on Micropatterned Surfaces to Optimize Hepatocyte Function

  2006cited by this paper
• Translation of research evidence from animals to humans.

  2006cited by this paper

• Comparative Evaluation of HepG2 Spheroid Generation Methods for Toxicology

  2026cites this paper
• A mechanistically-anchored and human stem cell-based in vitro test battery for assessing liver steatogenic potential of chemicals.

  2025cites this paper
• An Automated Imaging Method for Quantification of Changes to the Endomembrane System in Mammalian Spheroid Models

  2025cites this paper
• Effects of Benzo[k]fluoranthene at Two Temperatures on Viability, Structure, and Detoxification-Related Genes in Rainbow Trout RTL-W1 Cell Spheroids

  2025cites this paper
• Diallyl Disulfide Reduces Ethyl Carbamate-Induced Cytotoxicity and Apoptosis in Intestinal and Hepatic Cells

  2025cites this paper
• Mechanism-based new approach methodologies for in vitro detection of chemical-induced liver steatosis.

  2025cites this paper
• Induction of drug metabolizing enzyme and drug transporter expression by antifungal triazole pesticides in human HepaSH hepatocytes.

  2024cites this paper
• 1H NMR spectroscopic characterisation of HepG2 cells as a model metabolic system for toxicology studies.

  2024cites this paper
• Diosgenin Promoted Glucose Uptake by Attenuation of High Glucose Induced Blockade of PI3K-Akt-GLUT4 Pathway and ER Stress

  2024cites this paper
• The role of β2-AR/PI3K/AKT pathway in the proliferation, migration and invasion of THLE-2 cells induced by nicotine.

  2024cites this paper
• An automated high-content screening and assay platform for the analysis of spheroids at subcellular resolution

  2024cites this paper
• Trends in organ-on-a-chip for pharmacological analysis

  2024cites this paper
• Liver three-dimensional cellular models for high-throughput chemical testing.

  2023cites this paper
• HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds

  2023cites this paper
• Evaluating the Impact of Physiologically Relevant Oxygen Tensions on Drug Metabolism in 3D Hepatocyte Cultures in Paper Scaffolds

  2023cites this paper
• BDE-47-mediated cytotoxicity via autophagy blockade in 3D HepaRG spheroids cultured in alginate microcapsules.

  2023cites this paper
• Bioinspired Sandcastle Worm-Derived Peptide-Based Hybrid Hydrogel for Promoting the Formation of Liver Spheroids

  2022cites this paper
• The potential of organoids in toxicologic pathology: role of toxicologic pathologists in in vitro chemical hepatotoxicity assessment

  2022cites this paper
• Liver organ-on-chip models for toxicity studies and risk assessment.

  2022cites this paper
• Emerging trends in the methodology of environmental toxicology: 3D cell culture and its applications.

  2022cites this paper
• Establishing brown trout primary hepatocyte spheroids as a new alternative experimental model-Testing the effects of 5α-dihydrotestosterone on lipid pathways.

  2022cites this paper
• Modulating effect of Cu(II) complexes with enamine and tetrazole derivatives on CYP2C and CYP3A and their cytotoxic and antiproliferative properties in HepG2 spheroids

  2022cites this paper
• Cell Dome as an Evaluation Platform for Organized HepG2 Cells

  2022cites this paper
• Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development

  2022cites this paper
• Pengaruh Penggantian Medium terhadap Viabilitas Hepatosit Kultur 3D Organoid Hati

  2022cites this paper
• In Vitro Three-Dimensional Liver Models for Nanomaterial DNA Damage Assessment.

  2021cites this paper
• Mathematical modelling of oxygen gradients in stem cell-derived liver tissue.

  2021cites this paper
• Preparation of glutathione loaded nanoemulsions and testing of hepatoprotective activity on THLE-2 cells

  2021cites this paper
• Recent advances in the development of in vitro liver models for hepatotoxicity testing

  2021cites this paper
• Multiparametric nanoparticle-induced toxicity readouts with single cell resolution in HepG2 multicellular tumour spheroids.

  2021cites this paper
• Unit of Assessment: UOA11 Title of case study: Improving Drug Safety Screening: 3D – Liver Spheroid Toxicity Model Period when the underpinning research was undertaken: 2013-2017 Details of staff conducting the underpinning research from the submitting unit: Name(s):

  2021cites this paper
• Cell3: A new vision for study of the endomembrane system in mammalian cells.

  2021cites this paper
• Cell3: a new vision for study of the endomembrane system in mammalian cells

  2021cites this paper
• Complex Systems and Computational Biology Approaches to Acute Inflammation: A Framework for Model-based Precision Medicine

  2021cites this paper
• Mathematical modelling of oxygen gradients in stem cell-derived liver tissue 1

  2021cites this paper
• Testing methods and toxicity assessment (including alternatives)

  2020cites this paper
• RNA-protein correlation of liver toxicity markers in HepaRG cells

  2020cites this paper
• Multiscale modelling of drug transport and metabolism in liver spheroids

  2020cites this paper
• Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages

  2020cites this paper
• Hepato(Geno)Toxicity Assessment of Nanoparticles in a HepG2 Liver Spheroid Model

  2020cites this paper
• Utility of Three-Dimensional Cultures of Primary Human Hepatocytes (Spheroids) as Pharmacokinetic Models

  2020cites this paper
• Ultrastructural Features of Gold Nanoparticles Interaction with HepG2 and HEK293 Cells in Monolayer and Spheroids

  2020cites this paper
• Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

  2020cites this paper
• Characterization of In Vitro 3D Cell Model Developed from Human Hepatocellular Carcinoma (HepG2) Cell Line

  2020cites this paper
• Data-Driven Modeling of Liver Injury, Inflammation, and Fibrosis

  2020cites this paper
• Development of three-dimensional (3D) spheroid cultures of the continuous rainbow trout liver cell line RTL-W1.

  2019cites this paper
• Genetic toxicity assessment using liver cell models: past, present, and future

  2019cites this paper
• Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

  2019cites this paper
• Preparation of Primary Rat Hepatocyte Spheroids Utilizing the Liquid‐Overlay Technique

  2019cites this paper
• Decoding the secreted inflammatory response of primary human hepatocytes to hypoxic stress in vitro.

  2019cites this paper
• In silico-guided optimisation of oxygen gradients in hepatic spheroids

  2019cites this paper
• Environmental Toxicology and Chemistry

  2019cites this paper
• Mathematical modelling of a liver hollow fibre bioreactor.

  2019cites this paper
• A cell lines derived microfluidic liver model for investigation of hepatotoxicity induced by drug-drug interaction.

  2019cites this paper
• The comet assay applied to HepG2 liver spheroids.

  2019cites this paper
• Analysis of the cytotoxic, genotoxic, mutagenic, and pro-oxidant effect of synephrine, a component of thermogenic supplements, in human hepatic cells in vitro.

  2019cites this paper
• Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway.

  2019cites this paper
• Characterisation of a functional rat hepatocyte spheroid model

  2019cites this paper
• Challenges with risk mitigation in academic drug discovery: finding the best solution

  2018cites this paper
• Type of endothelial cells affects HepaRG cell acetaminophen metabolism in both 2D and 3D porous scaffold cultures

  2018cites this paper