Mechanisctic Toxicology - Research Groups

Group in Basel

Mechanistic toxicology (Alex Odermatt, co-applicant)
Our research focused on the elucidation of mechanisms of diseases associated with disturbed nuclear hormone receptor and pre-hormone receptor regulation. We described molecular defects of a renal glucocorticoid inactivating enzyme causing renal sodium retention and hypertension (6, 7). In addition, we studied the action of several environmental chemicals, food chemicals and drugs that interfere with glucocorticoid inactivation (8). Excessive glucocorticoid activation in liver and adipose tissue has been associated with metabolic disease. Inhibition of glucocorticoid activation in liver and adipose is therefore currently considered as promising therapy. We discovered alternative functions of the glucocorticoid activating enzyme in hepatic detoxification of oxidized cholesterol and in neurosteroid metabolism (9, 10). Our results emphasize the use of specific inhibitors for therapeutic purposes and reveal tissue- and species-specific properties of the enzyme that are crucial to understand its function in stress conditions and detoxification reactions. Using the glucocorticoid activating enzyme as a model, we investigate the polypharmacology of drugs by including targets for specificity analyses that were chosen based on sequence similarity, structural similarity or that share the same ligand. Proof-of-concept that structural similarity in the ligand binding pocket is important was demonstrated (11). Since drugs are usually not commercially available, we established a library of suspected endocrine disrupting chemicals (80’000 compounds), which is currently screened with pharmacophores of nuclear receptors and hormone metabolizing enzymes.

Last Updated on Thursday, 25 March 2010 15:38 Created: Thursday, 02 April 2009 15:33