Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project

Mueller, Stefan O.; Hewitt, Philip; Richert, Lysiane

doi:10.1016/j.tiv.2015.04.014

Cited by 11 publications

(10 citation statements)

References 68 publications

(68 reference statements)

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“…Cocultures and 3D cultures of hepatocytes that permit long-term compound exposure as well as inclusion of other liver nonparenchymal cell fractions increase the chances of detecting liver toxicants which typically escape conventional testing systems [ 21 , 29 , 30 , 95 ]. The choice of a particular model may be based on short-term versus long-term culture and the ability to study the toxicity of parent compounds or metabolites [ 96 ]. Finally, another aspect is how to address genetic variability in the patient populations.…”

Section: Lack Of Standardization In the Dili In Vitro Fieldmentioning

confidence: 99%

Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Atienzar

Blomme

Chen

et al. 2016

BioMed Research International

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Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.

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Section: Lack Of Standardization In the Dili In Vitro Fieldmentioning

confidence: 99%

Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Atienzar

Blomme

Chen

et al. 2016

BioMed Research International

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“…We will develop in vitro models of both steatosis (i.e., fat accumulation) and IR in HPR116 cells in the first three to four years of GOLIATH. Numerous investigations have been performed in HepaRG cells to study xenobiotic-induced toxicity and related mechanisms [42,[52][53][54]. More specifically, this cellular model has been used to study steatosis induced by different drugs known to be steatogenic in humans, including amiodarone, tamoxifen, tetracycline, and valproic acid [55][56][57].…”

Section: Steatosismentioning

confidence: 99%

The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

Legler

Zalko

Jourdan

et al. 2020

IJMS

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The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.

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“…This feature is essential for many pharmacological studies focused on the carcinogenic or transforming potential of xenobiotics. Using liver cancer cell line HepaRG, several studies showed a potential in pharmacological research (Antherieu et al, 2012;Szabo et al, 2013;Klein et al, 2014;Mueller et al, 2015;Tomida et al, 2015). However, due to the fact that HepaRG cells were derived from a hepatocarcinoma (Gripon et al, 2002) deficient in p53 functions (Cerec et al, 2007), this cell line might be less suited for some genotoxicity and tumorigenicity studies relying on nontransformed cells.…”

Section: Figurementioning

confidence: 99%

“…Physiologically relevant in vitro systems of human hepatocytes are of main interest to investigate the metabolite spectrum and potential hepatotoxicity of new drug candidates, as well as for basic biomedical research (Guillouzo and Guguen-Guillouzo, 2008;L€ ubberstedt et al, 2011;Mueller et al, 2015). Primary human hepatocyte (pHH) cultures are still the gold standard for pharmacological and toxicological investigations because they are considered the most appropriate in vitro model to study liver functions (Gomez-Lechon et al, 2004;LeCluyse et al, 2005;Li, 2015;Pfeiffer et al, 2015;Vildhede et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Primary‐like human hepatocytes genetically engineered to obtain proliferation competence display hepatic differentiation characteristics in monolayer and organotypical spheroid cultures

Herzog

Hansen

Miethbauer

et al. 2016

Cell Biology International

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Primary human hepatocytes are in great demand during drug development and in hepatology. However, both scarcity of tissue supply and donor variability of primary cells create a need for the development of alternative hepatocyte systems. By using a lentivirus vector system to transfer coding sequences of Upcyte® proliferation genes, we generated non-transformed stable hepatocyte cultures from human liver tissue samples. Here, we show data on newly generated proliferation-competent HepaFH3 cells investigated as conventional two-dimensional monolayer and as organotypical three-dimensional (3D) spheroid culture. In monolayer culture, HepaFH3 cells show typical cobblestone-like hepatocyte morphology and anchorage-dependent growth for at least 20 passages. Immunofluorescence staining revealed that characteristic hepatocyte marker proteins cytokeratin 8, human serum albumin, and cytochrome P450 (CYP) 3A4 were expressed. Quantitative real-time PCR analyses showed that expression levels of analyzed phase I CYP enzymes were at similar levels compared to those of cultured primary human hepatocytes and considerably higher than in the liver carcinoma cell line HepG2. Additionally, transcripts for phase II liver enzymes and transporter proteins OATP-C, MRP2, Oct1, and BSEP were present in HepaFH3. The cells produced urea and converted model compounds such as testosterone, diclofenac, and 7-OH-coumarin into phases I and II metabolites. Interestingly, phases I and II enzymes were expressed at about the same levels in convenient monolayer cultures and complex 3D spheroids. In conclusion, HepaFH3 cells and related primary-like hepatocyte lines seem to be promising tools for in vitro research of liver functions and as test system in drug development and toxicology analysis.

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Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project

Cited by 11 publications

References 68 publications

Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

Primary‐like human hepatocytes genetically engineered to obtain proliferation competence display hepatic differentiation characteristics in monolayer and organotypical spheroid cultures

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