A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity



Sison-Young, RL, Lauschke, VM, Johann, E, Alexandre, E, Antherieu, S, Aerts, H, Gerets, HHJ, Labbe, G, Hoët, D, Dorau, M
et al (show 13 more authors) (2017) A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity. Archives of Toxicology, 91 (3). 1385 - 1400.

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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.

Item Type: Article
Uncontrolled Keywords: pharmaceuticals, cytotoxicity, hepatocytes, predictive toxicology, toxicity, acute
Depositing User: Symplectic Admin
Date Deposited: 07 Apr 2017 14:26
Last Modified: 27 May 2020 10:07
DOI: 10.1007/s00204-016-1745-4
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3006887

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