Molecular Toxicology (Drug Disposition & Safety Assessment)

Molecular Toxicology (Drug Disposition & Safety Assessment)

In the specialization Molecular Toxicology (Drug Disposition & Safety Assessment) you will study the causes and effects of unwanted and sometimes toxic properties of drugs and substances. The research focuses on elucidating enzymes involved in bio-activation and on reactive metabolites responsible for toxicity of drugs and drug candidates. These studies will make it possible to develop safer drugs and to identify patient risk groups which may develop adverse drug reactions. Among various techniques you will use biochemical and analytical approaches.

Programme components

• Compulsory courses (36)
• Major research project (42)
• Literature thesis and colloquium (12)
• Ethics and academic skills (6)
• Elective: minor research project; abroad/company; optional courses (24)

Course overview

Research topics

In the specialisation Drug Disposition & Safety Assessment you can work on diverse research topics within the context of molecular toxicology.

Identification of molecular mechanisms and risk factors underlying adverse drug reactions
Idiosyncratic drug reactions are very rare and severe adverse drug reactions, which are only discovered after marketing of drugs. No animal models are yet able to predict these types of toxicity. It is hypothesized that reactive intermediates formed by hepatic cytochrome P450 enzymes are initiating this process, leading to severe drug-induced liver injury. We are currently developing analytical methods for the identification of reactive intermediates and their target proteins. Furthermore, we investigate whether genetically-determined enzymes (e.g. glutathione transferases (GSTs)) are involved in the formation and/or inactivation of reactive inter-mediates. These studies might explain which patient is susceptible to these life-threatening side-effects.

Development of novel in vitro models to studythe mechanism of drug-induced toxicity
To study the cellular responses caused by reactive drug metabolites, we are developing novel cellular toxicity model systems. We express different cytochromes P450s in these systems which may be involved in production of reactive drug metabolites. By studying the cellular responses caused by reactive metabolites, we want to characterize the critical cellular targets which are affected by reactive metabolites. Using yeast as a eukaryotic model, we recently identified specific components of the mitochondrial respiration chain as a target of hepatotoxins. These studies will be extended in human cell systems. By co-expressing individual GSTs we are studying their role in protection against cytotoxicity.

Novel biocatalysts for the production of humandrug metabolites and other fine-chemicals
Drug metabolites produced by cytochrome P450s can possess very potent pharmacological or toxicological activity. Therefore it is currently required that the properties of major human drug metabolites are tested individually. Since drug metabolites are often difficult to obtain by organic synthesis, we are developing novel biocatalysts which produce high levels of metabolite products. We use a combination of site-directed mutagenesis and random mutagenesis to create a library of catalyticaly diverse mutants of bacterial cytochrome P450 BM3. These mutants are capable to oxidize drugs and other fine-chemicals with high activity and with high regio and stereo selectivity. These studies – supported by biophysical and computational modeling studies – are aiming to obtain more fundamental insight into the mechanism of action of this highly important class of enzymes.

Contact

If you would like to know more about Molecular Toxicology (Drug Disposition & Safety Assessment), please contact the master coordinator:

Dr. Jan Commandeur
Phone: +31 20 59 87595
E-mail: j.n.m.commandeur@vu.nl