Molecular and cellular toxicology

Code: 64, study points: 3, period 1 (September: Monday and Tuesday).

Prof. dr. F.G.M. Russel, Department of Pharmacology and Toxicology, Radboud Institute of Moleculare Life Sciences,
Dr. J.B Koenderink, Department of Pharmacology and Toxicology, Radboud Institute of Molecular Life Sciences,

Insight into the harmful effects of pharmaceutical drugs and toxic compounds can only be achieved by understanding of the underlying molecular mechanisms. Disruption of cellular homeostasis upon toxicant exposure occurs often after interference with intracellular signalling pathways. Cell-surface or intracellular receptors that convert external stimuli into intracellular signals are pivotal in this signalling process. The resulting stress responses will translate injury into cellular death or repair programmes. In this module, the concepts of cellular toxicity are illustrated using kidney and brain as model target organs. As mitochondria are central in the coordination of cell-wide stress responses, the molecular mechanisms of mitochondrial toxicity will be studied. Special emphasis will be on the formation and inactivation of reactive intermediates (by cytochrome P450, glutathione S-transferases and other enzymes), their handling by cellular influx and efflux transporters, computational approaches to predict chemical toxicity, and the toxicological consequences of genetic polymorphisms of drug metabolising enzymes and transport proteins. Experimental and methodological approaches will be offered to quantitatively study the interaction of drugs and toxic compounds with a number of key molecular and cellular processes to understand and predict their cellular exposure and toxicity.
Main learning goals
After completion of the course, students are able to
1. Distinguish the molecular aspects of various toxicokinetic and toxicodynamic mechanisms underlying drug-induced toxicity.
2. Elucidate the molecular mechanism of toxicity induced by drugs and other chemicals that bind to different types of receptors.
3. Define biotransformation enzymes, and their role in bioactivation and bio-inactivation of drugs and other chemicals.
4. Explain the function of drug transport proteins and their role in drug-drug interactions.
5. Evaluate the risk factors, which might determine inter-individual susceptibility to drugs and other chemicals, including genetic polymorphisms, drug-drug interactions (inhibition, induction), environmental factors.
6. Apply the use of structure-activity relationship predictions in toxicology.
7. Comprehend methodological approaches to study the interference of drugs and other chemical compounds with key processes involved in cellular toxicity.