3 years ago

The Identification of Pivotal Transcriptional Factors Mediating Cell Responses To Drugs With Drug-Induced Liver Injury Liabilities.

Alex Medvedev, Marian Brodney, Liying Zhang, Sergei Makarov, Robert V Stanton, Falgun Shah, Anne Mai Wassermann
Drug-induced liver injury (DILI) is a leading cause of drug attrition during drug development and a common reason for drug withdrawal from the market. The poor predictability of conventional animal-based approaches (Olson et al. 2000) necessitates the development of alternative testing approaches. Body of evidence associates DILI with the induction of stress-response genes in the liver cells (Yuan and Kaplowitz 2013). Here, we set out to identify signal transduction pathways predominantly involved in the regulation of gene transcription by DILI drugs. To this end, we employed ATTAGENE's cell-based multiplexed reporter assay, the FACTORIAL TF™, that enables quantitative assessment of the activity of multiple stress-responsive transcription factors (TFs) in a single well of cells (Romanov et al., 2008). Using this assay, we assessed TF responses of a human hepatoma cell line HepG2 to a panel of 64 drug candidates, including 23 preclinical DILI and 11 clinical DILI compounds and 30 non-hepatotoxic compounds. We have identified 16 TF families that specifically responded to DILI drugs, including NRF2/ARE, Oct, HIF-1α, FXR, TCF/beta-catenin, AhR, AP-1, E2F, EGR-1, MTF-1, SREBP, Pax6, PPAR, LXR, IRF-1, and P53, and two promoters that responded to multiple TFs (CMV and DR3/VDR). These data demonstrate the utility of cost-effective, animal-free, TF profiling assay for detecting DILI potential of drug candidates at early stages of drug development.

Publisher URL: http://doi.org/10.1093/toxsci/kfx231

DOI: 10.1093/toxsci/kfx231

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