Rationale for the research area
The liver is one of the main targets of both pharmaceutical drugs and other chemicals (including alcohol). After oral ingestion, they can reach high concentrations in the liver and toxic metabolites can be produced. Drug-associated liver injury is one of the most important reasons for unsuccessful drug development or withdrawal from the market. A key step in liver injury is the excessive production of reactive oxygen species (ROS). Further characterisation of the key events determining the formation of ROS and the consequences of ROS formation for cells and organisms, in terms of cell function and survival, will increase the understanding of what leads to the adverse outcomes of liver injury and liver fibrosis.
This research area aims at understanding toxicity mechanisms related to perturbations in mitochondrial metabolism and Nrf2-signalling in order to identify potential susceptibility factors for liver toxicity, with liver injury/fibrosis as possible adverse outcomes. The research also attempts to identify and characterise key events mediating the transition from oxidative stress to liver damage.
Hepatotoxicity is an important concern during drug development. In the preclinical phase, potential hepatotoxicity can be detected using animals. Unfortunately, the mechanisms remain often unclear with this approach. The proposition is to construct cell models which allow conclusions concerning mechanisms and which can be used as routine tools in early drug development.