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A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
- Source :
- Archives of Toxicology
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1745-4) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Drug
Cytotoxicity
Health, Toxicology and Mutagenesis
media_common.quotation_subject
Cell
Acute
Pharmacology
Toxicology
030226 pharmacology & pharmacy
Organ Toxicity and Mechanisms
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
In vivo
Predictive toxicology
Toxicity Tests, Acute
Humans
Medicine
Cells, Cultured
media_common
Cryopreservation
Liver injury
Toxicity
business.industry
Reproducibility of Results
Hep G2 Cells
General Medicine
medicine.disease
In vitro
3. Good health
030104 developmental biology
medicine.anatomical_structure
Hepatocytes
Hepatic stellate cell
Pharmaceuticals
Chemical and Drug Induced Liver Injury
business
Subjects
Details
- ISSN :
- 14320738 and 03405761
- Volume :
- 91
- Database :
- OpenAIRE
- Journal :
- Archives of Toxicology
- Accession number :
- edsair.doi.dedup.....d335b3454c1138eac7bb8f92772b62d0