Groups in Basel

Research groups in Basel (1 in Bern)

Idiosyncratic organotoxicity (Stephan Krähenbühl, main applicant)
During the last 10 years, the focus of this group has been on the mechanisms and risk factors of idiosyncratic toxins, in particular toxins affecting the liver and/or skeletal muscle. Regarding mechanisms, a special field of interest was mitochondrial toxicity. We have described the effect of amiodarone and amiodarone derivatives on liver mitochondria and cultured hepatocytes (1). We have for instance explored the mechanism of hepatic toxicity of benzbromarone, which can cause a Reye syndrome-like type of hepatotoxicity in specific patients. Regarding amiodarone, we explored the possibility to separate mitochondrial toxicity from its pharmacological action (2). We have also described the toxicity of statins on isolated rat skeletal muscle mitochondria and on cultured myocytes (3). Statins are mitochondrial toxins, a finding possibly relevant for rhabdomyolysis associated with these drugs. Valproate is another drug we have investigated in detail. Based on clinical observations and laboratory investigations, we hypothesized that mitochondrial diseases are risk factors for hepatic toxicity of valproate (4). Most recently, we have described hepatotoxicity of valproate in an animal model with carnitine deficiency, supporting our hypothesis (5).

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.

In silico predictive toxicology (Angelo Vedani, co-applicant)
The VirtualToxLab is an in silico tool developed at the Biographics Laboratory 3R in Basel for predicting the toxic potential of existing and hypothetical chemicals. It simulates and quantifies their interactions with the human protein at the molecular level using automated, flexible docking combined with multi-dimensional QSAR (12-14). Currently, it includes 11 validated models for the aryl hydrocarbon, estrogen a/b, androgen, thyroid a/b, glucocorticoid, mineralocorticoid and peroxisome proliferator-activated receptor g as well as for the enzymes CYP450 3A4 and CYP450 2A13. The fully automated protocol is accessible through the Internet (for details, see http://www.biograf.ch). The technology has been validated using some 1,000 compounds binding to the 11 different macromolecular targets (15, 16).

Reproductive toxicology I (Christian De Geyter, co-applicant)
To overcome the problem of infertility after chemotherapy, we have performed a prospective feasibility study for the cryostorage of uninseminated oocytes and have achieved the first successful pregnancy with this method in Switzerland (17). However, with conventional freezing methods the pregnancy rates are low. An alternative strategy for preserving ovarian function could consist of cryostorage of oocytes and granulosa cells prior to chemotherapy and to reconstitute ovarian function after recovery from the malignant disease. Until recently, it was impossible to maintain ovarian granulosa cells in culture over prolonged time periods without loss of their main characteristics. Using granulosa cells taken from a granulosa cell tumor, our research unit was the first to produce an immortalized granulosa cell line (18). Further experiments have demonstrated that the antrum of a Graafian ovarian follicle contains a subset of undifferentiated stem cells, which retain all the characteristics of multipotent stem cells of the mesodermal lineage. We achieved to create a culture environment, in which a subpopulation of granulosa cells retained their characteristics, such as receptivity to FSH and their steroidogenic potential. This was achieved by culturing granulosa cells in a three dimensional scaffold on collagen I. With the support of the laboratory animal facilities at the University Hospital of Zürich three-dimensional collagen-granulosa scaffolds are now being transplanted into the ovaries of immuno-incompetent mice (nude mice). This experiment will demonstrate whether these granulosa cells, cultured over prolonged time periods in the presence of LIF, can reassume their function in their physiological niche. We have also studied to toxicity of chemo- and radiotherapy on spermatogenesis in humans (19).

Dermatotoxicology I (Andreas Bircher, co-applicant)
Our main focus in research is dermal toxicity, in particular hypersensitivity reactions to metals and other toxins (20, 21). Over the last years, we have built up a large database of patients with metal-associated hypersensitivity reactions to the skin. We are currently in the process of testing these patients with patch tests and at the same time with cellular in vitro methods to establish the prognostic value of these in vitro methods. One of the in vitro methods used is the lymphocyte transformation test, which we have developed further (22). We are also interested in the reaction patterns of dermal toxicity, which may also be of diagnostic value (23a).

Toxicopathology I (Luigi Terracciano, co-applicant)
The Institute for Pathology has specialists for the investigation of organ systems with clinical and toxicological relevance, including brain, heart, lung, liver, kidney, gastrointestinal tract, endocrine organs, urinary tract, prostate, bone marrow and lymphatic system, breast, ovary, bone and skin. Immunohistochemical analysis, electron microscopy and techniques in molecular pathology are used routinely. Yearly, the Institute analyses approximately 50,000 human tissue samples and 10,000 cytological smears from the above-mentioned organs. Based on a more than 50 years old tradition, there is precious knowledge about toxico-pathological problems such as toxicity of analgesics (so-called “Phenacetinniere”), calcineurin inhibitors (calcineurin inhibitor toxicity [CIN]) and others (23b, 23c). The Molecular Pathology Division of the Institute of Pathology has recently constructed tissue microarrays from more than 25’000 different tumors (23d). TMA technology has been extensively used in our Laboratory in cancer research, particularly for biomarker validation. It is obvious that this technique should also be applicable for toxicological studies early in drug development.

Lab-based clinical toxicology I (Manuel Haschke, Michael Bodmer, André Scholer, co-applicants)
During the last years, we have developed a library containing the fragmentation patterns of the most often observed toxins in patients attending the emergency unit of the University Hospital of Basel. This library contains, among others, the fragmentation patterns of most antidepressives, neuroleptics, benzodiazepines and opiates. The library is suitable for rapid detection and quantification of unknown toxins in intoxicated patients. This library needs completion and maintenance to fulfill its duties. We have developed an expert system for the localization of renal tubular damage using the protein excretion pattern in urine (24a). A similar system will be developed for the rapid diagnosis of intoxications in patients.

Immunotoxicology (Werner Pichler, co-applicant)
This research group is currently one of the leading groups in immunotoxicology in Europe. A special research focus is placed on drug- associated hypersensitivity syndromes, where the group made major contributions to the understanding of the mechanisms and classification of the disease (24b). The group proposed the p-i-concept, stating that direct activation of the T cell receptor by drugs is possible (no hapten formation is needed) (24c). Recent research shows that direct T cell receptor activation is probably one of the most important mechanisms of drug-associated hypersensitivity. Based on this concept, the group is trying to establish cellular systems for screening the allergenic potential of new drugs or drug candidates (24d).  

Last Updated on Monday, 30 March 2009 15:27 Created: Thursday, 05 February 2009 11:49