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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates glucocorticoid interactions with mineralocorticoid and glucocorticoid receptors in vivo, by converting 11 beta-hydroxyglucocorticoids to their inactive 11-ketone derivatives. Defective 11 beta-oxidation of glucocorticoids has been associated with hypertension. The objective of this study was to investigate whether 11 beta-HSD contributes to the occurrence of hypertension in spontaneously hypertensive rats (SHRs). The liver and kidney microsomal oxidations of corticosterone (the physiological glucocorticoid in rats) in organs from juvenile (3 weeks old) and adult (3 months old) SHR and Wistar-Kyoto (WKY) rats, with NAD and NADP, show no differences between rat strains. For cortisol, with NADP, adult SHRs show (1.3-3 times; P < 0.05) lower kidney microsomal oxidation rates. The liver microsomal reduction of cortisone shows remarkable interstrain differences; with NADH, reduction is conducted only by adult WKY rats, whereas with NADPH, juvenile animals show similar reduction rates, but at adulthood, only WKYs reduce cortisone. Using Western blot analysis with antibodies against 11 beta-HSD1, positive signals are obtained only for liver microsomes, appearing somewhat lower in SHRs for juvenile but not adult animals. Urinary corticosterone/11-dehydrocorticosterone ratios (measured in adult animals) are not different between rat strains, but are elevated after administration of corticosterone in both strains (although significant only in SHRs). The data provide no indications for exaggerated stimulation of renal corticosteroid receptors, due to modified 11 beta-HSD, in SHRs. However, the experiments suggest the existence of multiple 11 beta-HSDs, in addition to 11 beta-HSD1 and 11 beta-HSD2, some of which may be modified in SHR, but the nature and physiological role of these 11 beta-HSDs is unclear.
Steroids 1995 Nov
PMID:Comparison of 11 beta-hydroxysteroid dehydrogenase in spontaneously hypertensive and Wistar-Kyoto rats. 858 2

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
Steroids 1996 Apr
PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

The type 1 and type 2 isoforms of human 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) play a crucial role, respectively, in modulating glucocorticoid and mineralocorticoid hormone action. Deficiency of the 11 beta-HSD2 isoform, as described in the syndrome of apparent mineralocorticoid excess and following liquorice (glycyrrhetinic acid) or carbenoxolone ingestion, results in hypertension in which cortisol acts as a potent mineralocorticoid. Several studies have addressed the effects of progesterone, glycyrrhetinic acid, and their derivatives on 11 beta-HSD activity, but these were largely undertaken before the characterization of the 11 beta-HSD isoforms. The aim of this study was to evaluate the localization of 11 beta-HSD2 in human kidney and to study the effects of progesterone, glycyrrhetinic acid, and their related compounds on stable transfectants of the human 11 beta-HSD isoforms. Using an in-house sheep antibody against human 11 beta-HSD2, immunoperoxidase studies localized 11 beta-HSD2 to renal cortical and medullary collecting ducts. Glomeruli, vascular structures, loops of Henle, and proximal tubules were all negative. Confocal laser microscopy studies indicated both a cytoplasmic and nuclear localization for the enzyme within renal collecting ducts. The nuclear staining, which was intranuclear and was not associated with the nuclear membrane, accounted for 40% of the total cellular 11 beta-HSD2 immunoreactivity. Kinetic analysis of 11 beta-HSD activity in fetal kidney 293 cells stably transfected with h11 beta-HSD1/pcDNA3 or 11 beta-HSD2/pCR3, indicated, respectively, low-affinity dehydrogenase/oxoreductase activity (Km for F, 1.8 microM; Km for E, 270 nM) and high-affinity dehydrogenase activity (Km for F, 190 nM). The reductase activity of 11 beta-HSD1 was inhibited by 11 alpha-hydroxyprogesterone > carbenoxolone = glycyrrhetinic acid = progesterone > 11 beta-hydroxyprogesterone. The dehydrogenase activity of 11 beta-HSD2 was inhibited 11 alpha-hydroxyprogesterone = 11 beta-hydroxyprogesterone > glycyrrhetinic acid > carbenoxolone = progesterone. 11 beta-HSD2, expressed in the renal collecting duct, serves to protect the mineralocorticoid receptor (MR) in an autocrine fashion. The demonstration of a nuclear localization for what was thought to be principally a microsomal enzyme suggests that interaction between the MR and its ligand (either aldosterone or cortisol) may be a nuclear rather than a cytoplasmic event. The inhibitory effects of progesterone, glycyrrhetinic acid, and related compounds on 11 beta-HSD1 and 2 were similar, and it remains to be seen what implication these findings have for 11 beta-HSD1 action in tissues such as the liver and gonad and renal 11 beta-HSD2 activity in relation to sodium homeostasis and blood pressure control.
Steroids 1997 Jan
PMID:Human 11 beta-hydroxysteroid dehydrogenase: studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue. 902 19

We have previously reported that 5 alpha and 5 beta pathways of steroid metabolism are controlled in vivo by dietary Na+ and glycyrrhetinic acid, see Gorsline et al. 1988; Latif et al. 1990. The present investigations provide evidence supporting the suggestion that endogenous substances may regulate the glucocorticoid inactivating isoenzymes, 11 beta-HSD (hydroxysteroid dehydrogenase) 1 (liver) and 11 beta-HSD2 (kidney). The activity of 11 beta-HSD is impaired in essential hypertension, following licorice ingestion, and in patients with apparent mineralocorticoid excess where 11 beta-HSD2 is particularly affected. In all three conditions, excretion of the less common 5 alpha metabolites is elevated in urine. We now report on the differential abilities of a series of Ring A reduced (5 alpha and 5 beta) adrenocorticosteroid and progesterone metabolites to inhibit these isoenzymes. Using liver microsomes with NADP+ as co-factor (11 beta-HSD1), and sheep kidney microsomes with NAD+ as co-factor (11 beta-HSD2), we have systematically investigated the abilities of a number of adrenocorticosteroids and their derivatives to inhibit the individual isoforms of 11 beta-HSD. A striking feature is the differential sensitivity of the two isoenzymes to inhibition by 5 alpha and 5 beta derivatives. 11 beta-HSD1 is inhibited by both 5 alpha and certain 5 beta derivatives. 11 beta-HSD-2 was selectively inhibited only by 5 alpha derivatives: 5 beta derivatives were without inhibitory activity toward this isoform of 11 beta-HSD. These results indicate the importance of the structural conformation of the A and B Rings in conferring specific inhibitory properties on these compounds. In addition, we discuss the effects of additions or substitutions of other functional groups on the inhibitory potency of these steroid molecules against 11 beta-HSD1 and 11 beta-HSD2.
Steroids 1997 Feb
PMID:Selective inhibition of sheep kidney 11 beta-hydroxysteroid dehydrogenase isoform 2 activity by 5 alpha-reduced (but not 5 beta) derivatives of adrenocorticosteroids. 905 82

The 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme is responsible for the interconversion of glucocorticoids and their inactive metabolites, and thus modulates the intracellular level of bioactive glucocorticoids. The present study was designed to clone and characterize 11beta-HSD1 in the guinea pig, a laboratory animal known for resistance to glucocorticoids. The cDNA encoding guinea pig 11beta-HSD1 was cloned by a modified 3'-RACE (rapid amplification of cDNA ends) protocol using the hepatic RNA as template. The cloned cDNA encodes a protein of 300 amino acids that shares 71 to 74% sequence identity with other known mammalian 11beta-HSD1 proteins. Sequence comparison analysis revealed that the deduced guinea pig 11beta-HSD1 was longer, by eight amino acids at the C terminus, than those of other mammals. Moreover, one of the two absolutely conserved consensus sites for N-glycosylation was absent. To examine the functional significance of these structural changes, we also characterized 11beta-HSD1 activity in the hepatic microsomes. Although the guinea pig hepatic enzyme was NADP(H)-dependent and reversible, it displayed equal affinity for cortisol and cortisone (apparent K(m) for both substrates was 3 microM). This is in marked contrast to 11beta-HSD1 in other mammals whose affinity for cortisone is approximately 10 times higher than that for cortisol (apparent K(m) of 0.3 vs. 3.0 microM). The apparent lower affinity of the guinea pig enzyme for cortisone would suggest that the intracellular bioformation of cortisol from circulating cortisone may be less efficient in this species. Northern blot analysis and RT-PCR revealed that the mRNA for 11beta-HSD1 was widely expressed in the adult guinea pig but at low amounts. In conclusion, the present study has identified distinct features in the deduced primary structure and catalytic function of 11beta-HSD1 in the guinea pig. Thus, the guinea pig provides a useful model in which the structural determinants of catalytic function of 11beta-HSD1 may be studied.
Steroids 2000 Mar
PMID:Guinea pig 11beta-hydroxysteroid dehydrogenase type 1: primary structure and catalytic properties. 1069 94

The 11beta-hydroxysteroid dehydrogenase types 1 and 2 enzymes (11beta-HSD1 and 11beta-HSD2), modulate glucocorticoid occupation of the mineralocorticoid and glucocorticoid receptors by interconverting corticosterone and cortisol to the inactive metabolites 11-dehydrocorticosterone and cortisone within the target cells. The NAD(+)-dependent 11-HSD 2 in the kidney inactivates corticosterone and cortisol, allowing aldosterone, which is not metabolized, access to the receptor. Studies of the kinetics of 11-HSD 2 activity in the rat kidney have produced inconsistent results. Western blots done in the absence of the reducing agent beta-mercaptoethanol showed two bands with approximate MW of 40 and 80 kDa. When beta-mercaptoethanol was used, only the 40 kDa was detected, indicating that under non-denaturing conditions a significant proportion of the 11beta-HSD 2 exists as a dimer. NAD(+)-dependent conversion of 3H-corticosterone by 20 microg of microsomal protein increased approximately 10 fold with the addition of 5 mM DTT concentration. NADP(+)-dependent activity with 20 microg of microsomal protein was very low and did not change significantly when using DTT. In the presence of DTT, the predominant 11-HSD activity in the rat kidney is NAD(+)-dependent with a K(m) of 15.1 nM, similar to that of the cloned and expressed enzyme. These data suggest that dimerization and subsequent enzyme inactivation occur when protocols promoting oxidation of this protein are used.
Steroids 2001 Nov
PMID:The 11beta hydroxysteroid dehydrogenase 2 exists as an inactive dimer. 1157 24

Glucocorticoids (GC's) are metabolized in vascular tissue by two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD2 is unidirectional and metabolizes GC's to their respective inactive 11-dehydro derivatives. 11 beta-HSD1 is bi-directional, also possessing reductase activity and thus the ability to regenerate active GC from the 11-dehydro derivatives. In vascular tissue, GC's amplify the pressor responses to catecholamines and angiotensin II and may down-regulate certain depressor systems such as nitric oxide and prostaglandins. We hypothesize that both 11 beta-HSD2 and 11 beta-HSD1 regulate GC levels in vascular tissue and are part of additional mechanisms that control vascular tone. We examined the effects of specific antisense oligomers to 11 beta-HSD2 and 11 beta-HSD1 on GC metabolism and contractile response to phenylephrine (PE) in rat aortic rings. In aortic rings incubated (24 h) with corticosterone (B) (10 nmol/l) and 11 beta-HSD2 antisense (3 micromol/l), the contractile response to graded concentrations of PE (PE: 10 nmol/l - 1 micromol/l) were significantly (P < 0.05) increased compared to rings incubated with B and 11 beta-HSD2 nonsense. 11 beta-HSD1 antisense oligomers also enhanced the ability of B to amplify the contractile response to PE. In addition, 11 beta-HSD2 and 11 beta-HSD1 antisense also decreased the metabolism of B to 11-dehydro-B. 11-Dehydro-B (100 nmol/l) also amplified the contractile response to PE in aortic rings (P < 0.01), most likely due to the generation of active corticosterone by 11 beta-HSD1-reductase; this effect was significantly attenuated by 11 beta-HSD1 antisense. 11 beta-HSD1 antisense also caused a marked decrease in the metabolism of 11-dehydro-B back to B by 11 beta-HSD1-reductase. These findings underscore the importance of 11 beta-HSD2 and 11 beta-HSD1 in regulating local concentrations of GC's in vascular tissue. They also indicate that decreased 11 beta-HSD2 activity may be a possible mechanism in hypertension and that 11 beta-HSD1-reductase may be a possible target for anti-hypertensive therapy.
Steroids 2002 Mar
PMID:11 beta-Hydroxysteroid dehydrogenase antisense affects vascular contractile response and glucocorticoid metabolism. 1185 43

Steroids are implicated in many physiological processes, such as reproduction, aging, metabolism, and cancer. To understand the molecular basis for steroid recognition and discrimination, we studied the human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the bioactivation of all estrogens. Here we report the first observation of the conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta-diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century. Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta-diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The reduction of DHT was also observed in intact cells by using HEK-293 cells stably transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19-steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is reversibly oriented in the active site, which strongly supports the existence of alternative binding mode. Such a phenomenon can be explained by the pseudo-symmetric structure of C19-steroids. Our results confirm the role of the Leu149 residue in C18/C19-steroid discrimination and suggest a possible mechanism of 17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where both the enzyme and DHT are present.
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PMID:Pseudo-symmetry of C19 steroids, alternative binding orientations, and multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase. 1249 May 43

This study is concerned with an oral administration of 5mg of [1,2,4,19-13C(4),11alpha-2H]cortisol (cortisol-13C(4),2H(1)) to a human subject to reliably evaluate the individual activities of two isozymes of 11beta-HSD. The use of a GC-MS method allowed the simultaneous measurement of the plasma concentrations of cortisol-13C(4),2H(1), cortisone-13C(4), and cortisol-13C(4) together with endogenous cortisol and cortisone. The loss of 11alpha-2H during the conversion of cortisol-13C(4),2H(1) to cortisone-13C(4) by 11beta-HSD2 and the regenerated cortisol-13C(4) from cortisone-13C(4) by 11beta-HSD1 provided a direct and accurate means of distinguishing the activities of the two isozymes. The kinetic analysis associated with the metabolism of orally administered cortisol-13C(4),2H(1) was of great importance in assessing the 11beta-HSD activities. From a viewpoint of the chemical stability and much less pronounced kinetic isotope effect of the 13C-label and the 2H-labeling in the 11alpha-position, cortisol-13C(4),2H(1) used in this study served as an appropriate tracer for elucidating the kinetics of the interconversion of cortisol to cortisone in man.
Steroids 2003 Feb
PMID:Evaluation of 11beta-HSD activities in vivo following oral administration of cortisol-13C4,2H1 to a human subject. 1260 8

This study describes an oral administration of 5 mg of [1,2,4,19-13C4,11alpha-2H]cortisol (cortisol-13C4,2H1) to a human subject performed on two separate occasions, one with cortisol-13C4,2H1 alone and the other with cortisol-13C4,2H1 plus 130 mg per day of glycyrrhetinic acid for 6 days. The stable isotope methodology employed allowed for the evaluation of the individual in vivo activities of the two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), 11beta-HSD1 and 11beta-HSD2, and to demonstrate the sensitivity of changes in cortisol elimination half-life for detecting inhibition of 11beta-HSD2 activity induced with glycyrrhetinic acid. The kinetic analysis associated with the loss of 11alpha-2H during the conversion of cortisol-13C4,2H1 to cortisone-13C4 by 11beta-HSD2 clearly indicated reduced 11beta-HSD2 activity with glycyrrhetinic acid ingestion, as observed by an increase in the elimination half-life of cortisol-13C4,2H1. The elimination half-life of cortisol-13C4,2H1 provided sensitive in vivo measures of 11beta-HSD2 activity and was more sensitive for detecting changes in renal 11beta-HSD2 activity than the measurement of the urinary ratio of free cortisol and free cortisone (UFF/UFE). The 2H-labeling in the 11alpha-position of cortisol served as an appropriate tracer for assessing the reduced 11beta-HSD2 activity in vivo induced by glycyrrhetinic acid.
Steroids 2005 Feb
PMID:Use of 11alpha-deuterium labeled cortisol as a tracer for assessing reduced 11beta-HSD2 activity in vivo following glycyrrhetinic acid ingestion in a human subject. 1563 68


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