Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors

Objective: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. Design: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. Methods: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. Results: Progesterone and 11b-OH-progesterone (11b-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20a-dihydro(DH)-P, 5a-DH-P and 17a-OH-P had a 3-to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20a-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11b-OH-P, 11a-OH-P and 17a-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17a-OH-P and 20a-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. Conclusions: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17a-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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“…2A). A similar observation was made by Hellal-Levy et al (47). This suggests, similar to cortisol, a partial antagonist effect of DOC at the hMR.…”

Section: Doc and Hmrsupporting

confidence: 86%

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler

Meyer

Bumke-Vogt

et al. 2002

European Journal of Endocrinology

120

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“…One remarkable discrepancy is the MR binding affinity of cortisol being very close to that of aldosterone, while cortisol proved to be the weaker mineralocorticoid in terms of transactivation. Similar binding of aldosterone and cortisol to the hMR, but more potent transactivation via the MR by aldosterone, was described by Rupprecht et al (38) and Hellal-Lévy et al (43). The latter group showed that although the affinities for the MR are nearly the same, aldosterone dissociates much slower than cortisol from this receptor, and they assumed different induction of conformation changes of the MR by these ligands.…”

Section: -Ketosupporting

confidence: 64%

Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties

et al. 2004

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Background: Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco-and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable. Method: We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRa expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate). Results and Conclusions: While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the D1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16a-methyl or 16b-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone. The MC potency of a steroid is increased by a 9a-or a 6a-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9a-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.

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“…Second, the use of dexamethasone for glucocorticoid complementation prevented promiscuous activation of MR. Indeed, (1) because dexamethasone is approximately 100-fold more efficient than corticosterone for transactivating glucocorticoid receptors, 51 it could be administered at concentration of the same order as aldosterone, and (2) at this low concentration, even in the absence of 11␤-HSD2 activity, dexamethasone does not transactivate the MR because it is 1000-fold less efficient than aldosterone. 51 In summary, bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of Na ϩ ,K ϩ -ATPase in CCDs, to renal sodium retention and to ascites formation.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, (1) because dexamethasone is approximately 100-fold more efficient than corticosterone for transactivating glucocorticoid receptors, 51 it could be administered at concentration of the same order as aldosterone, and (2) at this low concentration, even in the absence of 11␤-HSD2 activity, dexamethasone does not transactivate the MR because it is 1000-fold less efficient than aldosterone. 51 In summary, bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of Na ϩ ,K ϩ -ATPase in CCDs, to renal sodium retention and to ascites formation. Sodium retention, ascites formation and induction of Na ϩ ,K ϩ -ATPase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids, supporting the "overflow theory" of sodium retention in liver cirrhosis in the cholestatic mice model.…”

Section: Discussionmentioning

confidence: 99%

Sodium retention and ascites formation in a cholestatic mice model

et al. 2007

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Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenalintact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodiumand potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium-and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum-and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium-and potassiumdependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. Conclusion: Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium-and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium-and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids. (HEPATOLOGY 2007;46:173-179.) See Editorial on Page 9 P atients with liver cirrhosis and portal hypertension develop renal sodium retention which promotes formation of ascites and peripheral edema. The "underfill theory" initially attributed sodium retention to secondary hyperaldosteronism accounted for by renal hypoperfusion brought about by intraabdominal fluid sequestration. 1 However, the underfill theory cannot explain the early phase of cirrhosis as sodium retention may precedes formation of ascites. 2-7 Thus, the "overflow theory" postulated that edema and ascites formation resulted from primary renal sodium retention promoting plasma volume expansion. 8 This theory is supported by the fact that abolishing portal hypertension in cirrhotic dogs by sideto-side portocaval shunt prevented ascites formation but not sodium retention. 5,6 Later, the "revised underfill theory" proposed that peripheral arterial vasodilatation leading to decreased effec...

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Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors

Cited by 159 publications

References 27 publications

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties

Sodium retention and ascites formation in a cholestatic mice model

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