Hepatotoxicity

Hepatotoxicity Service Overview

Drug induced liver injury (DILI) or hepatotoxicity is one of the leading causes of adverse events during clinical trials, which often results in failures or clinical holds during the development of new drug candidates, and even withdrawals from the market. With these factors in mind, early discovery of hepatotoxicity is essential to screening new drug candidates but poses many inherent challenges. DILI observed in a clinical setting is often idiosyncratic with undefined mechanism(s) of toxicity and low incidence rates, even in large populations. However, several mechanisms of DILI have been well-characterized and have the potential to be tested in a non-clinical setting or with in vitro tools.

Hepatotoxicity Methodologies
Available test systems in multi-well plates (e.g. 96-well)
Note: Cytoxicity assays can be adapted to non-hepatic cell lines (primary or immortalized) based on project needs and availablilty of cell lines.

Example cytotoxicity endpoints (including, but not limited to):
  • Evaluation of cell membrane integrity (e.g. by LDH [lactate dehydrogenase] release)
  • Mitochondrial respiration via measurement of indirect and direct loss of ATP production (e.g. ATP or reduction of resazurin)
  • Early or late apoptosis (e.g. caspase 3/7 or caspase 8/9 activities)
  • Glutathione (GSH) content or ratio of reduced to oxidized (GSH:GSSG)
  • qRT-PCR analysis of mRNA (single or multiple gene expression assays)
  • Other endpoints or mechanisms based on specific project needs through collaborators or commercial sources (e.g. project specific gene arrays)
Note: Evaluation of these endpoints is often time-dependent following treatment with compound(s). Incorporation of multiple time-points into the assay design is recommended in some cases.

For more information and example cytotoxicity data, view our flyer.
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Drug Induced Liver Injury (DILI) in Primary Hepatocytes
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Dose Response of DILI in Hepatocytes
Dose-Response-of-DILI-in-Hepatocytes-174.jpg
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