A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis

Tomida, Takafumi; Ishimura, Masakazu; Iwaki, Masahiro

doi:10.2131/jts.42.641

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…Full text of the remaining 125 articles were assessed for eligibility, being 67 studies excluded mainly due to: i) lack of DILI studies in in vitro human models, and ii) absence of hepatotoxicity assays. Furthermore, eight articles [33][34][35][36][37][38][39][40] that appeared to meet the inclusion criteria were excluded due to the detection of a bias in the selection of different drugs. In the hepatotoxicity assays, instead of selecting drugs with the potential to cause general DILI, the different articles focused on speci c DILI phenotypes, such as cholestatic, mitochondrial-induced DILI or drug-induced steatosis.…”

Section: Literature Searchmentioning

confidence: 99%

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Segovia-Zafra,

Villanueva-Paz,

Serras

et al. 2023

Preprint

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Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by different drugs, herbal, and dietary supplements. The early identification of human hepatotoxicity at the preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review aims to analyse the compounds used in hepatotoxicity assays and establish a unified list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by a committee of experts from the COST Action ProEuroDILI Network (CA 17112). This systematic review was performed in accordance with the 2020 PRISMA guidelines. Original research articles focused on investigating DILI occurrence using in vitro human models performing at least one hepatotoxicity assay with positive and negative control compounds were included. A modified version of the "Toxicological Data Reliability Assessment Tool" (ToxRTool) was used to assess the bias of the included studies. A total of 2,936 studies were retrieved from the different databases. Of these, 51 met the inclusion criteria, with 30 categorized as reliable without restrictions. Diclofenac and buspirone were the most commonly used DILI-positive and DILI-negative control drugs, respectively. Although there was a broad consensus on the positive compounds, the selection of negative control compounds remained less clear. Regarding the models used, the 2D monoculture of primary human hepatocytes (PHHs) was the favoured choice. However, there was no clear consensus on the drug concentrations. Short acute exposure times were mostly utilised, and cytotoxicity was the preferred endpoint. The extensive analysis of included studies highlighted the lack of agreement on appropriate control compounds for the in vitro assessment of DILI. Therefore, following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating new in vitro models for improving preclinical drug safety testing regimes.

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Section: Literature Searchmentioning

confidence: 99%

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Segovia-Zafra,

Villanueva-Paz,

Serras

et al. 2023

Preprint

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“…As the leakage is dependent on the milieu, difference in toxicity may appear if the material is tested as a solid surface in direct contact with the cells, or as an extract. 4,22,23 Testing materials by direct contact with cells has many drawbacks, for instance, large intrinsic variability due to the physical interference from the materials on the cell culture. Methods based on eluates of different kinds, are on the other hand less physiological in the sense that direct contact between materials and cells may be preferable.…”

Section: Test Materialsmentioning

confidence: 99%

Evaluation of cellular toxicity in Hep G2 cell and endothelial cells on different medical biopolymer supports

Fokunang¹

2018

MOJT

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Cellular responses to xenobiotic and environmental challenges are often cell cycle dependent and in view of the slow turn over in culture of endothelial cells, characterised by a long G1. In the context of the development of vascular models, a range of polyurethane materials as possible scaffolds and substrata have been evaluated for cell adhesion, proliferation and differentiation on the part of human hepatoma (HepG2) and endothelial cell. The aim of this study was to investigate the effect cell proliferation on toxicological end points. A comparison was made, for in vitro assessment of toxicity, between 12 polyurethanes (PU) [with respect to their cytocompatibility]. In our assessment growing population of cells were randomly grown on the different polyurethanes. Neutral red (NR), methy tetrazolium (MTT), and proliferation assays were used to determine the effect of exposure to test (polymer) and control surfaces. Results showed that there was generally a greater divergence between control and test responses for NR but not for MTT. NR proved more sensitive to extract exposure and this was significantly enhanced at a 1:3 medium ratio, rather than 1:1. For contact materials testing, the MTT response for HepG2 cells showed no correlation between synchronised and non-synchronised populations. Reproducibility and variate correlation was better for NR measures. Conclusion: Reduced surface affinity and growth kinetics on the part of Hep G2 and endothelial cells grown on CarbothaneTM, may be associated with deleterious events characteristic of an inflammatory response. A significant increase in the results was obtained where the cells exposed to some test polymers with cell viability increasing to 120-140% relative to control cell survival. The cell proliferation assay revealed significant differences for some of the test materials for synchronised and nonsynchronised cell populations.

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“…Tissue culture methods for assessment of toxicity of biomaterials have been used and established many years ago [22][23][24]. Many methodological efforts have been made to expose cells to the biomaterial in a way resembling an in vivo situation.…”

Section: Test Materialsmentioning

confidence: 99%

Evaluation of Cellular Toxicity in Hep G2 Cell and Endothelial Cells on Different Medical Biopolymer Supports

Fokunang

2018

JPCR

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Cellular responses to xenobiotic and environmental challenges are often cell cycle dependent and in view of the slow turn over in culture of endothelial cells, characterised by a long G1. In the context of the development of vascular models, a range of polyurethane materials as possible scaffolds and substrata have been evaluated for cell adhesion, proliferation and differentiation on the part of human hepatoma (HepG2) and endothelial cell. The aim of this study was to investigate the effect cell proliferation on toxicological end points. A comparison was made, for in vitro assessment of toxicity, between 12 polyurethanes (PU) [with respect to their cytocompatibility]. In our assessment growing population of cells were randomly grown on the different polyurethanes. Neutral Red (NR), Methy Tetrazolium (MTT), and proliferation assays were used to determine the effect of exposure to test (polymer) and control surfaces.Results showed that there was generally a greater divergence between control and test responses for NR but not for MTT. NR proved more sensitive to extract exposure and this was significantly enhanced at a 1:3 medium ratio, rather than 1:1. For contact materials testing, the MTT response for HepG2 cells showed no correlation between synchronised and non-synchronised populations. Reproducibility and variate correlation was better for NR measures. ConclusionReduced surface affinity and growth kinetics on the part of Hep G2 and endothelial cells grown on CarbothaneTM, may be associated with deleterious events characteristic of an inflammatory response. A significant increase in the results was obtained where the cells exposed to some test polymers with cell viability increasing to 120-140% relative to control cell survival. The cell proliferation assay revealed significant differences for some of the test materials for synchronised and non-synchronised cell populations.

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A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis

Cited by 5 publications

References 34 publications

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Evaluation of cellular toxicity in Hep G2 cell and endothelial cells on different medical biopolymer supports

Evaluation of Cellular Toxicity in Hep G2 Cell and Endothelial Cells on Different Medical Biopolymer Supports

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