Species-specific toxicity of troglitazone on rats and human by gel entrapped hepatocytes

Shen, Chong; Meng, Qin; Zhang, Guoliang

doi:10.1016/j.taap.2011.10.020

Cited by 13 publications

(8 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Culturing hepatocytes on dry stiff collagen induces resistance to TGF-β-induced apoptosis (Godoy et al 2009, 2010). A study comparing toxicity of troglitazone between gel-entrapped human and rat hepatocytes cultures demonstrated that human hepatocytes were more susceptible to the drug in this system compared to the rat hepatocytes, an effect not seen in monolayer culture (Shen et al 2012). …”

Section: Use Of In Vitro Systems For Predicting Liver Toxicitymentioning

confidence: 99%

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

Hewitt²,

et al. 2013

View full text Add to dashboard Cite

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 materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Use Of In Vitro Systems For Predicting Liver Toxicitymentioning

confidence: 99%

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

Hewitt²,

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Due to its central importance, any liver function impairment may lead to a range of deleterious illnesses and diseases. , Furthermore, many therapeutic drugs discovered in cell based assays result in hepatotoxicity in animal trials leading to high failure rates in drug approvals. This directly impacts the tremendous cost associated with drug discovery and may also result in the retrieval of existing drugs from the pharmaceutical market due to liver toxicity. , …”

Section: Introductionmentioning

confidence: 99%

Generation of a Scaffold-Free Three-Dimensional Liver Tissue via a Rapid Cell-to-Cell Click Assembly Process

et al. 2016

View full text Add to dashboard Cite

There has been tremendous interest in constructing in vitro liver organ models for a range of fundamental studies of cell signaling, metabolism, and infectious diseases, and as a commercial system to evaluate therapeutic drug discovery prioritization and toxicity. Although there has been progress toward studying two-dimensional hepatic function in vitro, there remain challenging obstacles to generate rapid and efficient scaffold-free three-dimensional multiple cell line coculture tissue models of liver. Herein, we develop and employ a strategy to induce specific and stable cell-cell contacts among multiple hepatic cell lines to generate 3D tissues through cell-surface engineering based on liposome delivery and fusion to display bio-orthogonal functional groups from cell membranes. We generate, for the first time, a three cell line coculture 3D liver tissue model by assembling hepatocytes, hepatic endothelial cells, and hepatic stellate cells via a rapid intercell click ligation process. We compare and analyze the function of the superior 3D liver tissue chips with 2D coculture monolayer by assessing mitochondrial metabolic activity and evaluating drug toxicity.

show abstract

“…Furthermore, the metabolic activity of liver‐on‐a‐chip was represented by the activity of CYP 1A2, 2E1, and 3A4, by the transformation of acetaminophen from phenacetin (Lu et al, 2008), 4‐nitrocatechol from 4‐nitrophenol (Shen, Zhang, Zhang, et al, 2006), and 6β‐hydroxy testosterone from testosterone (Shen et al, 2012). It was found that CYP activity in perfusion cultures was much higher than that in static cultures (Figure 6), suggesting the role of perfusion in CYP expression.…”

Section: Resultsmentioning

confidence: 99%

Hydrogel microfluidic‐based liver‐on‐a‐chip: Mimicking the mass transfer and structural features of liver

Meng

Wang

2020

Biotech & Bioengineering

Self Cite

View full text Add to dashboard Cite

Liver is fed by nutrition via diffusion across the vascular wall from blood flow. However, hepatocytes in liver models are directly exposed to the perfusion culture medium, where the shear stress reduces the cell viability and liver‐specific functions. By mimicking the mass transfer and structural features of hepatic lobule, we designed a microfluidic liver‐on‐a‐chip based on the di‐acrylated pluronic F127 hydrogel. In the hydrogel chip, hepatocellular carcinoma HepG2 and human hepatic stellate cell LX‐2 were statically cultured inside the microwells on the outer channel. These hepatic cells were fed by the diffused medium from the adjacent but separated inner channel with endothelial cell monolayers, which was perfused by the medium with physiologically relevant shear stress. As found, the hepatic cells in the liver‐on‐a‐chip rapidly formed spheroids within 1‐day incubation and expressed about one to two‐fold higher viability/liver‐specific functions than the corresponding static culture for at least 8 days. Moreover, the presence of endothelial cells also contributed to the expression of liver‐specific functions in the liver‐on‐a‐chip. Therefore, the proposed liver‐on‐a‐chip provides a new concept for construction of 3D liver models in vitro, and shows the potential value for a variety of applications including bio‐artificial livers and drug toxicity screening.

show abstract

Species-specific toxicity of troglitazone on rats and human by gel entrapped hepatocytes

Cited by 13 publications

References 38 publications

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

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

Generation of a Scaffold-Free Three-Dimensional Liver Tissue via a Rapid Cell-to-Cell Click Assembly Process

Hydrogel microfluidic‐based liver‐on‐a‐chip: Mimicking the mass transfer and structural features of liver

Contact Info

Product

Resources

About