Objective

Hepatic toxicity has accounted for 15 of the 47 drugs withdrawn from the market in the last two decades. More specifically, DILI is the major cause of acute liver failure in the USA and Europe and is one of the main reasons for regulatory actions. Although improvements have been made to cellular and animal models to predict intrinsic (dose dependent) DILI, it is almost impossible to predict idiosyncratic DILI. MH cells from MetaHeps have been developed as a tool to investigate long-term hepatotoxicity, metabolism and drug interactions. MH cells were used on a 96-well screening system that monitors changes in impedance (or cell monolayer resistance). Once the monolayer is exposed to a cytotoxic agent, the impedance changes and measures of toxicity can be quantified long-term. We investigated the hepatotoxic effects of paracetamol on MH cells when exposed for 24 and 48 hours. As expected, low doses of paracetamol caused transient toxicity and ‘adaptation’ was observed, whereas continued exposure to higher doses caused increased and irreversible hepatotoxicity.

In addition to hepatotoxicity, the device has also be used to investigate chronic proliferation of cancer cells. In this study, murine mammary carcinoma cells (H8N8 and H8N8 T3.2) were used and changes in impedance were used as a measure of toxicity. Intrinsic (dose-dependent) effects of a standard clinical treatment regimen could be identified as expected.