HepG2 cells | Human liver-derived cell line | Simple model | Low drug-metabolizing enzyme expression | Godoy et al. (2013), Atienzar et al. (2014, 2016) |
| | Suitable for short-term and longer-term studies | Poor expression of plasma membrane transporters | |
| | Multiple endpoints can be evaluated | | |
| | Suitable for high-volume and multiparametric data generation | | |
HepaRG cells | Human hepatoma-derived cell line | Can be differentiated into hepatocyte-like and biliary epithelial-like cells | Limited commercial availability | Guillouzo et al. (2007), Ott et al. (2017) |
| | Better maintenance of “hepatocyte-like” drug-metabolizing enzymes and membrane transporters than HepG2 cells | Complex cell culture conditions are needed | |
| | Multiple endpoints can be evaluated | Cells exhibit limited metabolizing enzyme phenotype | |
| | | P450 activities are lower than those in isolated primary hepatocytes | |
Cell lines expressing human P450s | Human liver-derived cell lines transfected with individual human P450s | Stably transfected cell lines are a simple model, well suited to multiparametric data generation plus acute and long-term toxicity studies | Transfected cell lines do not express hepatocyte-like cell phenotype, or many membrane transporters expression | Dambach et al. (2005), Hosomi et al. (2011), Tolosa et al. (2013), Gustafsson et al. (2014) |
| | Enable direct comparison between cell toxicity caused by parent compound (to mock-transfected cells) and metabolites (to transfected cells) | Unbalanced metabolism, since only selected P450s are expressed | |
Isolated hepatocytes | Isolated human hepatocytes | Freshly isolated hepatocytes express “in vivo–like” high drug metabolism activity | Limited availability of human donor livers | Hewitt et al. (2007), Xu et al. (2008); Usui et al. (2009), Ansede et al. (2010), Nakamura et al. (2010), Wolf et al. (2010), Thompson et al. (2012), Barber et al. (2015) |
| | Good maintenance of viability, for multiple days, when cultured as monolayers | Human liver exhibits marked interindividual variability | |
| | When cultured appropriately (ideally in sandwich configuration), regain polarized plasma membrane transporter expression and are well suited to multiparametric data generation | Freshly isolated hepatocytes in suspension are viable only for several hours and do not exhibit polarized plasma membrane transporter expression | |
| | | Longer-term hepatocyte culture is technically challenging and these cells fail to maintain high P450 expression | |
| | | Interindividual donor variability may influence results | |
Micropatterned hepatocyte/accessory cell cocultures | Isolated hepatocytes cocultured with macrophages or other accessory cells | Good maintenance of viability, drug-metabolizing enzymatic activity, and membrane transporters, for multiple days | Technically challenging to prepare; commercial supply is required | Underhill and Khetani (2017) |
| | Numerous endpoints can be evaluated, at a single cell level | Limited variety and physiologic relevance of accessory cells | |
| | | Limited toxicity characterization | |
| | | Interindividual donor variability may influence results | |
Liver microtissues (spheroids) | Liver cell aggregates, which includes hepatocytes and multiple nonparenchymal cell types | Good maintenance of viability, drug-metabolizing enzyme activity, and membrane transporters, for multiple days | Technically challenging to prepare; commercial supply is required | Bell et al. (2016), Proctor et al. (2017) |
| Limited toxicity characterization | |
| Endpoints cannot be quantified at a single cell level | |
| Interindividual donor variability may influence results | |
Microfluidic devices | Hepatocytes, multiple liver cell types, or liver-derived cell line devices that reproduce in vivo oxygen tension gradients and/or fluid flow | Improved maintenance of viability and drug-metabolizing enzyme activity, and membrane transporters, for multiple days, compared with nonmicrofluidic cell models | Technically challenging to prepare; commercial supply of devices is required | Vernetti et al. (2016) |
| | | Limited toxicity characterization | |
| | | Interindividual donor variability may influence results | |
Stem cell–derived hepatocytes | Hepatocytes or other differentiated human liver cells, generated via stem cell technology | If successful, could provide cells in large amounts that replace a need for cell isolation from human donor livers | Complex cell differentiation protocols are required | Goldring et al. (2017) |
| | | Currently available conditions provide poorly differentiated cells | |
| | | Limited toxicity characterization | |