PhD conferral Angelina Huseinovic
Aula, Vrije Universiteit Amsterdam
Mistaken identity: Paracetamol induces amino acid starvation through mimicry of tyrosine and changes ubiquitin homeostasis
Prof.Dr. N.P.E. Vermeulen, copromotoren Dr. J.M. Kooter & Dr.Ir. J.C. Vos
Amsterdam Institute of Molecular and Life Sciences
Paracetamol is a widely used analgesic and antipyretic drug, and generally considered safe at therapeutic concentrations. However, high doses and/or prolonged use may cause serious side effects, such as liver- and renal toxicity. These side effects are mainly caused by the action of the toxic metabolite NAPQI, which is formed in the liver by Cytochrome (CYP) P450 enzymes. Besides this metabolism-dependent toxicity, Paracetamol can also be toxic without the bioactivation to NAPQI. The mechanism of this metabolism-independent toxicity is still not well understood, however.
The main aim of my PhD research was to study in yeast possible links between the yeast genotype and paracetamol-induced toxicity, this in order to get a better insight into the mechanisms of NAPQI-independent toxicity of Paracetamol with the final goal to translate the findings from yeast to human. For this purpose, we performed a genome-wide chemogenomic screen using a collection of Saccharomyces cerevisiae deletion strains, chemogenomic profiling and functional yeast studies. Interestingly, the results revealed a significant and novel role of the ubiquitin-proteasome system and of amino acids availability in the susceptibility to Paracetamol toxicity. The current findings are novel and an important step into a better understanding of the toxicity of the parent Paracetamol in humans.
Model to illustrate the stress response caused by Paracetamol in yeast. Paracetamol causes tryptophan starvation by mimicking tyrosine, which leads to a ubiquitin dependent nutrient starvation response and growth arrest. Ubiquitin deficient strains avoid growth arrest due to the absence of necessary genes.
The digital thesis can be found here.