Original ArticlesMetabolism of Synthetic Corticosteroids by 11β-hydroxysteroid-Dehydrogenases in Man
Introduction
The 11β-hydroxyl group is essential for the glucocorticoid (GC) and mineralocorticoid (MC) activity of endogenous and synthetic steroids.1., 2. 11-Dehydrosteroids bind poorly to GC-3 and MC-receptors.4 For immunosuppressive effects within a target organ, local rather than systemic concentrations of active 11-hydroxysteroids determine biologic effectiveness.5., 6. For the individual cell, plasma concentrations are a measure only of the extracellular supply of active GCs. The ultimate biologic effect, i.e., access of the 11-hydroxysteroid to the nucleus, may also be regulated by a transport system into the cell or/and by local biotransformation.2 Thus, 11β-hydroxysteroid-dehydrogenases (11β-HSDs) are very important, as they convert active GCs to inactive 11-dehydroproducts.7., 8. Recently, two isoenzymes of 11β-HSD have been characterized and cloned in human tissues9., 10. as well as in tissues of several other species. The isoenzyme 11βHSD-I is widely distributed, prefers NADP(H) as cosubstrate, and has low substrate affinity for endogenous GCs (Km value in the micromolar range).9., 11. In vitro, 11β-HSD-I functions as a bidirectional enzyme. In vivo, it seems to be mainly a reductase.12., 13. The isoenzyme 11β-HSD-II seems to exclusively oxidize physiological GCs, uses NAD as cosubstrate, is found in MC target tissues (kidney, colon, salivary glands) and placenta, and shows a high substrate affinity for endogenous GCs (Km values in the nanomolar range).10., 14. The physiological function of the 11β-HSD-II is the protection of MC receptors from cortisol (F), thus allowing MC access by aldosterone. In addition to this well-described function of 11β-HSD-II, both isoenzymes modulate GC access to GC receptors in the different organs.2 As the metabolism of synthetic GCs by these enzymes seems to be very important for optimizing sytemic GC and MC therapy, we summarize our studies on the metabolism of synthetic 9α-fluorinated steroids by 11β-HSDs in man in vivo and in vitro.
Section snippets
In vivo
After suppression of endogenous corticosteroid production by dexamethasone pretreatment (1 mg at midnight and 0.5 mg at 0600 h), five healthy young men took 5 mg of cortisol (F), 5 mg of 9α-fluorocortisol (9αFF), 4 mg of 9α-fluorocortisone (9αFE), or placebo on different days at 0800 h. Urine was collected in four fractions, and free steroids were measured by an online high-performance liquid chromatography (HPLC) sytem described previously.15., 16. All human subjects had given written informed
In vivo
After pretreatment with dexamethasone alone (placebo), urinary F, E, and other corticosteroids were below the detection limit of the method (5 nmol/L). After administration of 5 mg of F (following dexamethasone), ∼70% of the free steroid fraction in urine was E, whereas ∼30% was F (Figure 1 ). After ingestion of 5 mg of 9αFF, ∼90% of the free fraction appeared unaltered in the urine, and ∼10% was the dehydroproduct 9αFE. Following the administration of 5 mg 9αFF orally, the cumulative
9α-fluorocortisol versus cortisol (in vivo and kidney slices)
9αFF is used for MC substitution in patients with Addison’s disease and with isolated hypoaldosteronism. In vivo, 9αFF is 200–400 times more potent than cortisol (F) as a MC.22 Surprisingly, in a cell-free sytem, 9αFF, F, and aldosterone have the same affinity for the MC receptor.16., 23. The in vivo GC potency of 9αFF is about 5- to 20-fold greater than that of F,24 but it cannot be used for systemic GC therapy given its predominant MC effect.
After oral administration of F, ∼70% of the free
Acknowledgements
The authors thank Dr. H. Laurent and Dr. H. J. Zentel (Schering AG, Berlin) for providing unlabeled DH-D and Dr. F. Brehme (Institute of Pharmacology, Freie Universität Berlin) for performing mass-spectometric analysis of the synthesized tritiated DH-D. We also thank Prof. P. Neuhaus (Dept. of Surgery, Klinikum Rudolf Virchow, Humboldt Universität Berlin) for providing human liver tissue and P. Exner for excellent analytical assistance in the laboratory.
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2016, Asian Pacific Journal of ReproductionCitation Excerpt :Glucocorticoids are crucial for development of embryo and their bioactivity is modulated by the intracellular metabolism including 11β-hydroxysteroid dehydrogenases (11β-HSDs) and 20-hydroxysteroid dehydrogenase (20-HSD) [77]. The 11β-HSD1 activates, whereas 11β-HSD2 inactivates GCs in mammals including man, mice and in vitro [78–82]. The 11β-HSD1 is expressed predominantly in mouse liver, kidney and lung of mice [83], while 11HSD2 mainly exists in kidney, colon and placenta of the human [84].
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2016, Asian Pacific Journal of ReproductionCitation Excerpt :The intracellular concentrations of active GC are under control of a number of metabolizing enzymes which is called pre-receptor modulation [17]. The 11β-hydroxysteroid dehydrogenase (11β-HSD1) activates, while 11β-hydroxysteroid dehydrogenase (11β-HSD2) deactivates GCs [18–22]. In avian species, 20-hydroxysteroid dehydrogenase (20-HSD) is an abundantly and ubiquitously expressed enzyme, which transforms GCs to inactive 20-dihydrocorticosterone [23].
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2013, Comparative Biochemistry and Physiology - A Molecular and Integrative PhysiologyCitation Excerpt :The intracellular level of active GC is regulated by a number of GC metabolizing enzymes (Edwards et al., 1996). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates, whereas 11β-HSD2 inactivates GCs (Diederich et al., 1998; Stewart and Krozowski, 1999; Harris et al., 2001; Holmes et al., 2003; Holmes and Seckl, 2006). In mammals, 11β-HSD1 is expressed predominantly in the liver, kidney and lung (Rajan et al., 1995), while 11β-HSD2 mainly exists in the kidney, colon and placenta (Albiston et al., 1994).