Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes

Oorts, Marlies; Baze, Audrey; Bachellier, Philippe; Heyd, Bruno; Zacharias, Thomas; Annaert, Pieter; Richert, Lysiane

doi:10.1016/j.tiv.2016.03.008

Cited by 57 publications

(57 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies on sandwich-cultured hepatocytes (SCH) demonstrated higher toxicity of CS and GB in the presence than in the absence of BA. In our study, CS concentrations that led to the decrease in viability and increase in intracellular BA concentrations were two- to threefolds lower (Chatterjee et al 2014b ; Ogimura et al 2011 ; Oorts et al 2016 ) than that found with rat or human SCH. In PCLS, IC 50 values of CP and GB in the presence of BA were similar to (for CP) or 1.5–3-folds higher (for GB) than those in rat SCH (Chatterjee et al 2014b ; Ogimura et al 2011 ).…”

Section: Discussioncontrasting

confidence: 45%

“…Thus, in vitro tests with high predictive value that also provide insight into the mechanism are highly needed. Some in vitro models have been developed to predict drug-induced cholestasis, based on hepatocyte sandwich monocultures (Chatterjee et al 2014a , b ; Oorts et al 2016 ). However, the decrease in drug-metabolizing enzyme activities and the variation in the expression of drug transporters during culture, affects the predictivity and reliability of this model.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rat precision-cut liver slices predict drug-induced cholestatic injury

et al. 2017

View full text Add to dashboard Cite

Drug-induced cholestasis (DIC) is one of the leading manifestations of drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not fully known and specific and predictive biomarkers and pre-clinical models are lacking, the occurrence of DIC is often only reported when the drug has been approved for registration. Therefore, appropriate models that predict the cholestatic potential of drug candidates and/or provide insight into the mechanism of DIC are highly needed. We investigated the application of rat precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of cholestasis: hepatocyte viability, intracellular accumulation of total as well as individual bile acids and changes in the expression of genes known to play a role in cholestasis. Rat PCLS exposed to the cholestatic drugs chlorpromazine, cyclosporine A and glibenclamide for 48 h in the presence of a 60 μM physiological bile acid (BA) mix reflected various changes associated with cholestasis, such as decrease in hepatocyte viability, accumulation and changes in the composition of BA and changes in the gene expression of Fxr, Bsep and Ntcp. The toxicity of the drugs was correlated with the accumulation of BA, and especially DCA and CDCA and their conjugates, but to a different extent for different drugs, indicating that BA toxicity is not the only cause for the toxicity of cholestatic drugs. Moreover, our study supports the use of several biomarkers to test drugs for DIC. In conclusion, our results indicate that PCLS may represent a physiological and valuable model to identify cholestatic drugs and provide insight into the mechanisms underlying DIC.

show abstract

Section: Discussioncontrasting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Rat precision-cut liver slices predict drug-induced cholestatic injury

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Therefore, we studied the suitability of the PHH and HepaRG spheroid systems to identify compounds with cholestatic liability. Since it was recently shown that compounds with known cholestatic liability and an externally added mixture of BAs pose selective synergistic toxicity in sandwich-cultured hepatocytes 27 28 , we employed the strategy of using compound and BA co-exposures to identify compounds with cholestatic risk.…”

Section: Resultsmentioning

confidence: 99%

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

Hendriks

Puigvert

Messner

et al. 2016

Sci Rep

127

View full text Add to dashboard Cite

Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability.

show abstract

“…Hepatocyte-ECM interaction provides polarity in hepatocytes and can be modeled as a sandwich culture by culturing hepatocytes between the two layers of ECM. Such platform has served as a tool for analysis of long-term hepatocytes function and drug-induced toxicity assays [162][163][164].…”

Section: Classical Animal Modelsmentioning

confidence: 99%

Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies

Heydari

Najimi

Mirzaei

et al. 2020

Cells

View full text Add to dashboard Cite

Organ and tissue shortage are known as a crucially important public health problem as unfortunately a small percentage of patients receive transplants. In the context of emerging regenerative medicine, researchers are trying to regenerate and replace different organs and tissues such as the liver, heart, skin, and kidney. Liver tissue engineering (TE) enables us to reproduce and restore liver functions, fully or partially, which could be used in the treatment of acute or chronic liver disorders and/or generate an appropriate functional organ which can be transplanted or employed as an extracorporeal device. In this regard, a variety of techniques (e.g., fabrication technologies, cell-based technologies, microfluidic systems and, extracorporeal liver devices) could be applied in tissue engineering in liver regenerative medicine. Common TE techniques are based on allocating stem cell-derived hepatocyte-like cells or primary hepatocytes within a three-dimensional structure which leads to the improvement of their survival rate and functional phenotype. Taken together, new findings indicated that developing liver tissue engineering-based techniques could pave the way for better treatment of liver-related disorders. Herein, we summarized novel technologies used in liver regenerative medicine and their future applications in clinical settings.

show abstract

Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes

Cited by 57 publications

References 61 publications

Rat precision-cut liver slices predict drug-induced cholestatic injury

Rat precision-cut liver slices predict drug-induced cholestatic injury

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies

Contact Info

Product

Resources

About