An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for
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IN VITRO SYSTEMS
An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma‑derived cells for predicting drug‑induced liver injury Shingo Oda1 · Yuka Uchida1 · Michael D. Aleo2,5 · Petra H. Koza‑Taylor2 · Yusuke Matsui3 · Masanori Hizue4 · Lisa D. Marroquin2 · Jessica Whritenour2 · Eri Uchida4 · Tsuyoshi Yokoi1 Received: 2 April 2020 / Accepted: 13 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Preventing clinical drug-induced liver injury (DILI) remains a major challenge, because DILI develops via multifactorial mechanisms. Immune and inflammatory reactions are considered important mechanisms of DILI; however, biomarkers from in vitro systems using immune cells have not been comprehensively studied. The aims of this study were (1) to identify promising biomarker genes for predicting DILI in an in vitro coculture model of peripheral blood mononuclear cells (PBMCs) with a human liver cell line, and (2) to evaluate these genes as predictors of DILI using a panel of drugs with different clinical DILI risk. Transcriptome-wide analysis of PBMCs cocultured with HepG2 or differentiated HepaRG cells that were treated with several drugs revealed an appropriate separation of DILI-positive and DILI-negative drugs, from which 12 putative biomarker genes were selected. To evaluate the predictive performance of these genes, PBMCs cocultured with HepG2 cells were exposed to 77 different drugs, and gene expression levels in PBMCs were determined. The MET proto-oncogene receptor tyrosine kinase (MET) showed the highest area under the receiver-operating characteristic curve (AUC) value of 0.81 among the 12 genes with a high sensitivity/specificity (85/66%). However, a stepwise logistic regression model using the 12 identified genes showed the highest AUC value of 0.94 with a high sensitivity/specificity (93/86%). Taken together, we established a coculture system using PBMCs and HepG2 cells and selected biomarkers that can predict DILI risk. The established model would be useful in detecting the DILI potential of compounds, in particular those that involve an immune mechanism. Keywords Cell-based assay · Coculture · Drug-induced liver injury · Immune reaction · Peripheral blood mononuclear cells
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02882-4) contains supplementary material, which is available to authorized users. * Shingo Oda [email protected]‑u.ac.jp 1
Division of Clinical Pharmacology, Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai‑cho, Showa‑ku, Nagoya 466‑8550, Japan
2
Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
3
Laboratory of Intelligence Healthcare, Nagoya University Graduate School of Medicine, Nagoya, Japan
4
Drug Safety Research and Development, Pfizer Inc, Tokyo, Japan
5
Present Address: TOXinsights LLC, East Lyme, CT, USA
Introduction Drug-induced liver injury (DILI) is an advers
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