Multiparametric assay using HepaRG cells for predicting drug-induced liver injury.

Abstract:

:The utility of HepaRG cells as an in vitro cell-based assay system for assessing drug-induced liver injury (DILI) risk was investigated. Seventeen DILI-positive and 15 DILI-negative drugs were selected for the assay. HepaRG cells were treated with each drug for 24h at concentrations that were 1.6-, 6.3-, 25-, and 100-fold the therapeutic maximum plasma concentration (Cmax). After treatment, the cell viability, glutathione content, caspase 3/7 activity, lipid accumulation, leakage of lactate dehydrogenase, and albumin secretion were measured. The sensitivity and specificity were calculated to assess the ability of the assay to predict DILI. Our multiparametric assay using HepaRG cells exhibited a 67% sensitivity and 73% specificity at a 100-fold concentration of Cmax and a 41% sensitivity and 87% specificity at a 25-fold concentration of Cmax. When a 25-fold Cmax cut-off was applied, approximately 70% of drugs exhibiting positive responses were classified into the high DILI risk category. HepaRG cells distinguished relatively safe drugs from their high-risk analogs. Our study indicates that HepaRG cells may be of use to (1) prioritize drug analogs, (2) analyze the mechanism of DILI, and (3) assess the risk for DILI in the early drug discovery stage.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Tomida T,Okamura H,Satsukawa M,Yokoi T,Konno Y

doi

10.1016/j.toxlet.2015.04.014

subject

Has Abstract

pub_date

2015-07-02 00:00:00

pages

16-24

issue

1

eissn

0378-4274

issn

1879-3169

pii

S0378-4274(15)00150-2

journal_volume

236

pub_type

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