Journal article
Integration of in vitro data from three dimensionally cultured HepaRG cells and physiologically based pharmacokinetic modeling for assessment of acetaminophen hepatotoxicity
Regulatory toxicology and pharmacology, Vol.114, pp.104661-104661
07/2020
DOI: 10.1016/j.yrtph.2020.104661
PMID: 32315674
Abstract
Selection of appropriate fit-for-purpose in vitro and in silico models is critical for non-animal safety assessment of chemical-induced hepatoxicity. The present study evaluated the feasibility of integrating in vitro data from three-dimensionally (3D)-cultured HepaRG cells and physiologically based pharmacokinetic (PBPK) modeling to predict chemical-induced liver toxicity. A 3D organoid culture system was established using an ultralow attachment method. HepaRG cells cultured in a two-dimensional (2D) monolayer and under 3D conditions were exposed to acetaminophen (APAP) at concentrations of 0.16–20 mM. The results showed that the viability of both 3D- and 2D cultured cells was significantly decreased by APAP in a concentration-dependent manner. Furthermore, 3D cultures were more sensitive to APAP-induced mitochondrial damage than 2D cultures were, based on measurements of mitochondrial superoxide accumulation and mitochondrial membrane potential loss. PBPK simulations using nominal in vitro concentrations showed that the APAP concentration eliciting mitochondrial damage was closer to the predicted peak liver concentration in humans in 3D cultures than it was in 2D cultures. In summary, our results suggest that combining in vitro data from 3D HepaRG cultures and PBPK modeling provides a promising tool for assessment of liver injury.
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•Formation of 3D HepaRG organoid culture.•Comparsion of APAP induced toxicity in 3D/2D HepaRG cells.•Establishment of PBPK modeling of APAP.•Integration of PBPK modeling with in vitro data.
Details
- Title: Subtitle
- Integration of in vitro data from three dimensionally cultured HepaRG cells and physiologically based pharmacokinetic modeling for assessment of acetaminophen hepatotoxicity
- Creators
- Chi Zhang - Academy of Military Medical SciencesQiang Zhang - Emory UniversityJin LiLin Yu - Academy of Military Medical SciencesFengxiang Li - Center of Disease Control and Prevention, PLA, Beijing, PR ChinaWeiwei Li - Guiyang Medical UniversityYujie Li - Center of Disease Control and Prevention, PLA, Beijing, PR ChinaHui Peng - Center of Disease Control and Prevention, PLA, Beijing, PR ChinaJun Zhao - Center of Disease Control and Prevention, PLA, Beijing, PR ChinaPaul L. Carmichael - University of BedfordshireYunfang Wang - Academy of Military Medical SciencesShuangqing Peng - Academy of Military Medical SciencesJiabin Guo - Academy of Military Medical Sciences
- Resource Type
- Journal article
- Publication Details
- Regulatory toxicology and pharmacology, Vol.114, pp.104661-104661
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.yrtph.2020.104661
- PMID
- 32315674
- ISSN
- 0273-2300
- eISSN
- 1096-0295
- Grant note
- name: National Key Research and Development, award: 2018YFC1602602; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81430090; name: Unilever International Collaborative Project, award: MA-2015-00410
- Language
- English
- Date published
- 07/2020
- Academic Unit
- Neurology
- Record Identifier
- 9984303017402771
Metrics
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