A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk

J Appl Toxicol. 2017 Mar;37(3):382-390. doi: 10.1002/jat.3371. Epub 2016 Aug 2.

Abstract

The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty-eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100-fold the therapeutic maximum plasma concentration (Cmax ). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut-off values of each parameter, the TC50 (toxic concentration that decreased the response by 50%) and EC200 (effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut-off: score ≥ 1; area under a receiver operating characteristic curve (ROC-AUC): 0.88], and for WDN and BW categories (cut-off: score ≥ 3; ROC-AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: HepaRG cells; drug-induced liver injury; hepatotoxicity; multiparametric assay; toxicity score.

MeSH terms

  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / pathology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Biological*
  • Pharmaceutical Preparations* / classification
  • Predictive Value of Tests
  • Risk Assessment
  • Sensitivity and Specificity

Substances

  • Pharmaceutical Preparations