Seibert, Julia Katharina. Characterization of the 11β-hydroxysteroid dehydrogenase 1-related short-chain dehydrogenase/reductase DHRS7. 2015, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11333
In another study, the effects of 11β-aminoprogesterone derivatives were evaluated for their potential to inhibit 11βHSD2 in vitro. Inhibition of 11βHSD2 is usually avoided in the development of pharmaceuticals, since its systemic inhibition causes sodium and water retention, elevated blood pressure and hypokalemia. Nevertheless, selective 11βHSD2 inhibition has been suggested as a potential therapy for hemodialysis patients suffering from hyperkalemia or for patients with colon cancer. Thus, we tested a series of progesterone derivatives in bioassays and six of them showed selective inhibition of 11β-HSD2 over 11β-HSD1. These compounds offer a good basis for the development of 11β-HSD2 inhibitors with optimized properties for topical applications. However, risk-benefit analysis as well as comparison with other potential selective inhibitors needs to be done. Thus, the assessment of the therapeutic potential of 11β-aminoprogesterone derivatives warrants further research.
The assessment of 11βHSD inhibitors in vivo requires analytical methods to detect changes in steroid levels. Therefore, another aim of this thesis was to establish an LC-MS/MS method to quantify corticosteroid hormones. The method was applied in a clinical study on the effects of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) and the cognitive enhancer Methylphenidate (MPH) on circulating steroid hormones in healthy subjects. The serotonin releaser MDMA showed acute effects on circulating steroids. MDMA significantly increased the plasma concentrations of cortisol by more than 60% compared to control. These effects were not observed with MPH, which stimulates the dopamine and norepinephrine systems. Thus, the findings of this study support the view that serotonin mediates the acute pharmacologically induced stimulation of the Hypothalamic–pituitary–adrenal (HPA) axis in the absence of other stressors. Since cortisol was elevated but cortisone levels were not altered, an effect on the activities of the glucocorticoid metabolizing 11β-HSD1 and 11β-HSD2 triggered by MDMA and/or MPH could not be fully excluded.
The last and main part of this thesis focused on the “orphan” SDR DHRS7. Given that more than 70 SDRs have been discovered in humans and almost half of them have not been characterized, some “orphan” SDRs may be important therapeutic targets and others may represent “off-targets” if inhibited unintentionally by pharmaceuticals. Hence, “deorphanizing” enzymes is crucial to understand their physiological roles and to evaluate and understand adverse and beneficial drug effects. In this thesis the SDR DHRS7 was identified as a tumor suppressor and possible marker for breast and prostate cancer. DHRS7 protein was found to be decreased with increasing tumor grades in prostate cancer tissue samples. Furthermore, knockdown of DHRS7 increased the aggressiveness of cells in vitro. Microarray data suggested the involvement of EMT and/or the BRCA pathway in the DHRS7 mediated effects. In addition, evidence presented in this thesis suggests DHRS7 may also play a role in liver regeneration. To fully understand the mechanism and function of DHRS7 its substrate(s) need to be identified. Applying our steroid analytics the most common steroid hormones could be excluded as substrates of DHRS7 and further research is warranted to “deorphanize” this enzyme. An untargeted omics approach is currently followed for hypothesis generation.
In conclusion, the results presented in this thesis significantly extend our knowledge in the field of SDRs. Firstly, we identified novel, potent, selective inhibitors for two well-characterized 11βHSDs. Secondly, the observed effects of amphetamine-related drugs on steroid hormone levels in the blood suggest that they activate the HPA axis and enhance steroid production rather than altering steroid levels by modifying 11βHSD activities. Finally, this thesis describes a novel role for the “orphan” SDR DHRS7 as a tumor suppressor in breast and prostate cancer. This thesis underlines the importance of “deorphanizing” SDRs, which may play important roles in many metabolic and signaling pathways and may thus be involved in several diseases.
|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:||96 Bl.|
|Last Modified:||30 Jun 2016 10:57|
|Deposited On:||26 Aug 2015 15:09|
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