Meyer, Arne. The role of the endoplasmic reticulum in the metabolism of "xenobiotica". 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10385
11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the conversion of the active glucocorticoid cortisol to the inactive cortisone. It has been reported that some organotins and dithiocarbamates are potent inhibitors of human 11β-HSD2. We found that the zebrafish enzyme is not inhibited by these organotins. Furthermore, the dithiocarbamate thiram showed a reduced inhibitory effect on zebrafish 11β-HSD2 compared with the human enzyme. Sequence comparison revealed the presence of an alanine at position 253 on zebrafish 11β-HSD2, corresponding to cysteine-264 in the substrate binding pocket of the human enzyme. Substitution of alanine-253 by cysteine resulted in a more than 10-fold increased sensitivity of zebrafish 11β-HSD2 to thiram. These findings are important, as the zebrafish is a widely used model in ecotoxicology, and 11β-HSD2 is catalyzing the conversion of 11β-hydroxytestosterone to 11-ketotestosterone, the main androgen in fish.
The gene encoding 11β-HSD1 in zebrafish is absent. Therefore, the mechanism how the ratio between active and inactive glucocorticoids is controlled in fish is unclear. It was suggested by a phylogenetic analysis that one of the two ancestors of 11β-HSD1 might reduce cortisone to cortisol. These ancestors are 11β-HSD3a and 11β-HSD3b. We cloned both zebrafish cDNAs and tested them for 11-oxosteroid reductase activity. Furthermore, we examined the metabolism of cortisone in zebrafish microsomes. Our results indicate that the 11-oxosteroid reductase activity is completely absent in zebrafish.
17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) catalyzes the conversion of Δ4-androstenedione to testosterone. We reported earlier that some UV filters inhibit the human enzyme. We tested whether these UV filters also inhibit the zebrafish enzyme. We found interesting species-specific differences of the inhibitory potential of UV filters on human and zebrafish 17β-HSD3. Furthermore, we were able to show additive inhibitory effects of UV filter mixtures and bioaccumulation of UV filters in vitro.
In conclusion, the results presented in this thesis significantly extend the knowledge of the role of 11β-HSD1 in the metabolism of xenobiotics. The thesis further emphasizes the importance of considering species-specific differences when trying to extrapolate effects of xenobiotics observed in animal models to humans.
|Committee Members:||Arand, Michael|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||143 Bl.|
|Last Modified:||30 Jun 2016 10:53|
|Deposited On:||27 Jun 2013 10:25|
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