Session: SAT 358-380-Steroid Hormone Biosynthesis & Metabolism
Poster Board SAT-364
Cortisol is firstly inactivated by oxidation to cortisone by 11β-HSD type 2. Recently, we have identified an enzyme putatively involved in further catabolic steps of cortisol inactivation in zebrafish. This enzyme, the 20β-HSD type 2, catalyzes the conversion of cortisone to 20β-hydroxycortisone . Here, we demonstrate that treatment of zebrafish larvae with the stress hormone cortisol significantly up-regulated the transcription of both 11β-HSD type 2 and 20β-HSD type 2, while the protein level of 20β-HSD type 2 was also increased. In contrast, upon cortisol treatment the activity of 20β-HSD type 2 was found to be decreased. This effect was explained by an inhibition of the 20β-HSD type 2 activity by the artificially high cortisol concentrations in our experimental arrangement. An acute swirling stress was as well able to up-regulate both 11β-HSD type 2 and 20β-HSD type 2. Morpholino-induced 20β-HSD type 2 knock-down larvae showed a diminished capability to cope with excess cortisol. Reporter gene experiments demonstrated that 20β-hydroxycortisone is a ligand for neither the glucocorticoid nor the mineralocorticoid receptor. The analysis of excreted glucocorticoids in fish holding water revealed 20β-hydroxycortisone to be labeled with glucuronic acid and sulfate residues, indicating its function as excretion product.
To our knowledge, an ortholog of zebrafish 20β-HSD type 2 in humans has not yet been discovered. However, our analyses of glucocorticoids in urine identified 20β-hydroxycortisone to be an excretion product in humans as well.
Our results suggest that the oxidation of cortisol to cortisone by 11β-HSD type 2 and the subsequent reduction of cortisone to 20β-hydroxycortisone by 20β-HSD type 2 represent a novel pathway for the inactivation of cortisol and its subsequent excretion not only in zebrafish but probably as well in humans. Both enzyme activities might therefore be of high importance in silencing the cortisol signal upon stress.
 Tokarz J, Mindnich R, Norton W, Möller G, Hrabe de Angelis M, Adamski J (2012): Discovery of a novel enzyme mediating glucocorticoid catabolism in fish: 20beta-hydroxysteroid dehydrogenase type 2, Molecular and cellular endocrinology 349 (2) 202-213
Nothing to Disclose: JT, WN, GM, MH, JA
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