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Arch Toxicol. 2018 Jan;92(1):383-399. doi: 10.1007/s00204-017-2036-4. Epub 2017 Jul 31.

Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury.

Author information

1
Unidad de Hepatología Experimental, Torre A, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av Fernando Abril Martorell 106, 46026, Valencia, Spain. laiatolosa@hotmail.com.
2
Unidad de Hepatología Experimental, Torre A, Instituto de Investigación Sanitaria La Fe (IIS 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 de Investigación Sanitaria La Fe (IIS 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) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI. To this end, HepG2 cells with different expression levels of specific drug-metabolism enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, GSTM1 and UGT2B7) were exposed to nine drugs with reported hepatotoxicity. A panel of pre-lethal mechanistic parameters (mitochondrial superoxide production, mitochondrial membrane potential, ROS production, intracellular calcium concentration, apoptotic nuclei) was used. Significant differences were observed according to the level of expression and/or the combination of several drug-metabolism enzymes in the cells created ad hoc according to the enzymes implicated in drug toxicity. Additionally, the main mechanisms implicated in the toxicity of the compounds were also determined showing also differences between the different types of cells employed. This screening tool allowed to mimic the variability in drug metabolism in the population and showed a highly efficient system for predicting human DILI, identifying the metabolic phenotypes associated with increased DILI risk, and indicating the mechanisms implicated in their toxicity.

KEYWORDS:

CYP; Cell model; Drug-induced liver injury; Hepatotoxicity mechanisms; Idiosyncrasy

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