HEPATOTOXICITY

Hepatoxicity is the leading cause of late-stage drug attrition, accounting for approximately 30% all drug withdrawals. To better predict the potential hepatotoxic effects of lead compounds, Fluofarma developed a set of assays based on polarized primary hepatocytes. This highly relevant model, which retains in vivo - like features, is optimized for high-throughput screening, for fast and accurate hepatotoxicity testing.

In addition to hepatoma cell lines, Fluofarma performs primary cultures of rat and human hepatocytes for toxicology studies.

Primary hepatocytes cultured in sandwich configuration display in vivo - like features:

> Better maintenance of drug-metabolizing enzymes

> Formation of bile canaliculi network

Live content imaging enables to accurately determine the safety profile of lead compounds.

Kinetic monitoring of hepatotoxic effects over several days also ensures that no drug effects remained unnoticed over that period.

> Dynamic monitoring of hepatocyte viability over several days

> Accurate time-dependent EC50 values

> Time & cost-efficient : less wells, more data

Fluofarma offers to assess potential hepatotoxic effects on key liver functions by automated high-content imaging & flow cytometry, using the following functional cell-based assays:

> Lipid accumulation

> Bile canaliculi toxicity (in polarized primary hepatocytes cultures)

> Redox state

> LDL uptake

> Intracellular Ca2+

> NADH/FAD content

> Cytolysis

> Mitochondrial toxicity

Fluofarma can correlate hepatotoxic effects observed in living cells with markers of specific signaling pathways involved in detoxification and oxidative stress.

For instance, the NRF2 pathway, can be studied by quantifying the expression level of Nrf2 targets, such as:

> Heme oxygenase 1 (Ho-1)

> Quinone oxidoreductase-1 (Nqo1)

> Multidrug-resistant proteins (MRPs)