APAP induced liver injury (DILI)
Drug Induced Liver Injuries: Studying the underlying mechanisms
Drug-induced liver injury (DILI) is a term that describes abnormalities in liver function tests (LFTs) related to medication intake. Acetaminophen (APAP), a widely used analgesic and antipyretic drug considered to be safe at therapeutic doses, whereas overdoses result in increased induction of hepatotoxicity. Although APAP intoxication is generally associated with the formation of reactive metabolites, oxidative stress and mitochondrial dysfunction, the mechanisms are still not fully understood. This project aims to explore the underlying mechanisms of drug induced liver injures by using APAP as a model compound.
Over the last 5 to10 years the use of genomics and metabolomics, so called ‘omics technologies, in toxicology has increased tremendously. These techniques can be used to evaluate or monitor the impact of exposure to xenobiotics on human health. Moreover, these techniques could possibly be used as a tool for chemical risk assessment in humans. Accumulated evidences have revealed that activation of immune responses and the release of pro-inflammatory cytokines have been characterized in APAP-induced acute liver injury and hepatic failure. In addition, in vivo ‘omics’ data from both mice and rats after APAP exposure demonstrate that both APAP exposure show a similar toxicity response including a loss in functionality of the mitochondria and an increase in oxidative stress. However, data collected from human liver samples after toxic-dose APAP exposure are rare.
In this study, several in vitro models, such as 3D co-culture of human liver cells in a 3D matrix will be developed. Genetic features of 2D, 3D and human liver models after exposure to the toxic dose of APAP will be profiled on a genome-wide level. Moreover, multiple phenotypical endpoints will also be measured to further understand underlying mechanisms of the toxic dose of APAP induced liver injury and identify the possibility of using ‘omics’ technologies as a chemical risk assessment tool for humans.
Click here to watch a 3D vizualization of the mechanism.
Click here to download the 2015 SOT poster.