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Arch Toxicol. 2019 Feb;93(2):519-532. doi: 10.1007/s00204-018-2349-y. Epub 2018 Nov 13.

Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes.

Author information

1
Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain. laiatolosa@hotmail.com.
2
Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain.
3
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain.
4
Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain. donato_mte@gva.es.
5
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain. donato_mte@gva.es.

Abstract

Drug-induced liver injury (DILI) constitutes one of the most frequent reasons of restricted-use warnings as well as withdrawals of drugs in postmarketing and poses an important concern for the pharmaceutical industry. The current hepatic in vivo and in vitro models for DILI detection have shown clear limitations, mainly for studies of long-term hepatotoxicity. For this reason, we here evaluated the potential of using Upcytes human hepatocytes (UHH) for repeated-dose long-term exposure to drugs. The UHH were incubated with 15 toxic and non-toxic compounds for up to 21 days using a repeated-dose approach, and, in addition to conventional examination of effects on viability, the mechanisms implicated in cell toxicity were also assessed by means of high-content screening. The UHH maintained the expression and activity levels of drug-metabolizing enzymes for up to 21 days of culture and became more sensitive to the toxic compounds after extended exposures, showing inter-donor differences which would reflect variability among the population. The assay also allowed to detect the main mechanisms implicated in the toxicity of each drug as well as identifying special susceptibilities depending on the donor. UHH can be used for a long-term repeated detection of DILI at clinically relevant concentrations and also offers key mechanistic features of drug-induced hepatotoxicity. This system is therefore a promising tool in preclinical testing of human relevance that could help to reduce and/or replace animal testing for drug adverse effects.

KEYWORDS:

Cell model; Chronic toxicity; Hepatotoxicity; Mechanisms; Preclinical evaluation

PMID:
30426164
DOI:
10.1007/s00204-018-2349-y

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