UMLS:C0432222 - FACTA Search

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Query: UMLS:C0432222 (SEM)
47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major site of cortisol metabolism in man has been thought to be the liver. Studies in patients with either congenital or acquired deficiency of 11 beta-hydroxysteroid dehydrogenase (an enzyme responsible for the interconversion of cortisol to cortisone) suggested that the kidney was an important site of cortisone production. In 88 patients with proven renal disease but normal liver function, arbitrarily divided into four groups on the basis of plasma creatinine, 0900 h plasma cortisone was significantly reduced in all groups when compared with 47 controls (e.g. 21 +/- 3 nmol/l (mean +/- SEM) in patients with plasma creatinine greater than 0.45 mmol/l vs 62 +/- 3 nmol/l in controls, P less than 0.001). 0900 h plasma cortisol was not significantly different. There was an inverse correlation between plasma creatinine and plasma cortisone (r = -0.55, p less than 0.01). Four anephric patients had a 0900 h plasma cortisone level of 6 +/- 1 nmol/l. We conclude that the kidney is a major site for the conversion of cortisol to cortisone and hence cortisone production in man. The relevance of this to the pathophysiology of salt and water metabolism in renal disease remains to be elucidated.
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PMID:The kidney is the major site of cortisone production in man. 262 Apr 65

A method for the quantitative estimation of 11 beta-hydroxysteroid dehydrogenase activity (11 beta-HSD; EC.1.1.146) in human placental homogenates is described. This method is based on the separation of cortisol and cortisone by high performance liquid chromatography after extraction from homogenates incubated in the presence of cortisol and NADP. 11 beta-HSD activity (pmol/g wet weight per min) averaged 900 +/- 150 (mean +/- SEM) at 10 +/- 2 weeks of gestation, 915 +/- 35 at 17 +/- 2 weeks and 790 +/- 42 at 40 +/- 2 weeks, thus supporting the view that the placenta is an effective barrier to materno-fetal cortisol transfer throughout gestation.
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PMID:11 beta-Hydroxysteroid dehydrogenase activity of the human placenta during pregnancy. 346 74

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of glycyrrhizic acid (glycyrrhizin), an important constituent of licorice and licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, or 1500 mg) were administered to healthy volunteers in order to study its kinetics and dynamics. In agreement with the lipophilic nature of GRA, with a biphasic decay of the plasma concentration-time curve at doses greater than 500 mg. The mean (+/-SEM) half-life of the second elimination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with increasing GRA doses. Urinary elimination of GRA and GRA glucuronides over 24 h was less than 1% of the dose administered. The dynamics of GRA were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, and the cortisol/cortisone ratio increased. Both peak plasma concentration and AUCs of GRA correlated with changes in the AUC values of cortisone. Based on the single dose kinetics, the kinetic/dynamic analysis of the data revealed that after multiple doses of 1.5. g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently.
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PMID:Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans. 812 29

An experiment was conducted in pigs to determine the source of fetal cortisol at 50 (n = 5) or 100 days (n = 4) of gestation (term = 114 days). Equilibrium concentrations of tritiated cortisol were achieved, and all hormonal measures were made at 110, 130, 140, and 150 min in anesthetized pigs. Maternal plasma cortisol did not differ (p = 0.48) between 50 (70.2 +/- 7.4 ng/ml; mean +/- SEM) and 100 days (62.4 +/- 5.8 ng/ml). Conversely, fetal cortisol increased (p = 0.048) between 50 (8.5 +/- 2.5 ng/ml) and 100 days (24.2 +/- 4.2 ng/ml), and, at each gestational age, values were lower (p = 0.001) than those in maternal plasma. Plasma cortisone (15.1 +/- 2.3 ng/ml) did not change with gestational age (p = 0.42) in either compartment (maternal or fetal), nor did it differ between compartments (p = 0.08). Maternal cortisol accounted for 22.8 +/- 2.0% of fetal cortisol at 50 days of gestation, and this contribution decreased (p < 0.001) to 5.87 +/- 0.8% at 100 days. At both ages, maternal cortisol accounted for almost 50% of fetal cortisone. Metabolism of maternal cortisol by the entire uterofetoplacental unit was 8.4 +/- 1.7% at 50 days and 7.5 +/- 2.4% at 100 days (p = 0.76). The maternal metabolic clearance rate of cortisol increased 44% (p = 0.003) between 50 and 100 days (1.49 +/- 0.4 vs. 2.15 +/- 0.2 L/min). Hence at these gestational ages, the fetus--presumably the fetal adrenal--is the primary source of fetal plasma cortisol. The major contribution of maternal cortisol to fetal cortisone strongly suggests the presence of porcine placental 11 beta-hydroxysteroid dehydrogenase activity. Further, factors constituting the placental "barrier" that metabolize maternal cortisol to cortisone and other products may be major regulators of porcine fetal plasma cortisol and cortisone.
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PMID:Placental metabolism of cortisol at mid- and late gestation in swine. 856 84

Glucocorticoid action in several target tissues is dependent on expression of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), and in the placenta 11 beta-HSD is thought to regulate transfer of active glucocorticoid to the fetus. This study compared expression of the two recognized 11 beta-HSD enzymes, types 1 and 2, in the rat placenta and decidua on Days 16 and 22 of gestation (term = Day 23). According to S1 nuclease protection analysis, although mRNA for 11 beta-HSD-1 was only just detectable in the labyrinth zone on Day 16, by Day 22 this expression had increased almost 20-fold. There was also an increase (approximately 2-fold) in 11 beta-HSD-1 mRNA in the basal zone between Days 16 and 22. In Day 16 decidua, 11 beta-HSD-1 mRNA was also highly expressed, but insufficient tissue was available for analysis on Day 22. Western blot analysis showed that immunoreactive 11 beta-HSD-1 (molecular mass 34 kDa) was present in those tissues with the highest 11 beta-HSD-1 mRNA expression (Day 16 decidua and Day 22 labyrinth zone). With respect to mRNA for 11 beta-HSD-2, high expression was observed in the decidua and labyrinth zone at Day 16, but in the latter this expression then declined 90% by Day 22. In contrast, expression of mRNA for 11 beta-HSD-2 increased more than 3-fold in the basal zone over the same period. Consistent with coexpression of the two 11 beta-HSD enzymes, both 11-oxoreductase and 11 beta-dehydrogenase bioactivity were clearly evident in all tissues, and each varied with stage of gestation. Specifically, 11 beta-dehydrogenase activity in the basal zone increased from 38 +/- 2% (mean +/- SEM) on Day 16 to 56 +/- 2% on Day 22, while 11-oxoreductase activity fell from 55 +/- 3% to 43 +/- 2% over the same period. In contrast, 11 beta-dehydrogenase activity in the labyrinth zone fell with advancing pregnancy (Day 16: 63 +/- 2%; Day 22: 48 +/- 2%). Both 11-oxoreductase (58 +/- 3%) and 11 beta-dehydrogenase (38 +/- 4%) activities were also evident in decidua at Day 16. In conclusion, this study shows that expression of 11 beta-HSD-1 and -2 is zone-specific in the placenta and maternal decidua. Moreover, opposite changes in the expression of the two enzymes occur in the basal and labyrinth zones of the placenta over the last days of pregnancy, indicative of distinct regulatory mechanisms and functional significance for the enzymes in the two placental zones.
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PMID:Zonal distribution of 11 beta-hydroxysteroid dehydrogenase types 1 and 2 messenger ribonucleic acid expression in the rat placenta and decidua during late pregnancy. 890 13

We have proposed that the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) of Leydig cells protects against glucocorticoid-induced inhibition of testosterone (T) production. However, Leydig cells express type I 11 beta-HSD, which has been shown to be reductive in liver parenchymal cells. Because reduction would have the opposite effect of activating glucocorticoid, the present study was designed to determine: 1) whether Leydig cell 11 beta-HSD is primarily oxidative or reductive; and 2) whether oxidative and reductive activities are separately modified by known regulators of Leydig cell steroidogenic function. Leydig cells and liver parenchymal cells were purified from mature male Sprague-Dawley rats (250 g BW), and 11 beta-HSD oxidative and reductive activities were measured using radiolabeled substrates and TLC of triplicate media samples from 1-h incubations immediately after cell isolation. Enzyme activities also were examined in purified Leydig cells at the end of 3 days of culture in vitro in the presence of LH (10 ng/ml), dexamethasone (DEX, 100 nM), T (50 nM), or epidermal growth factor (EGF, 50 ng/ml). In confirmation of previous reports, the reductive activity of 11 beta-HSD was predominant over oxidation in liver parenchymal cells. In contrast, 11 beta-HSD oxidative activity prevailed over reduction in Leydig cells by a ratio of 2:1. The activities of 11 beta-HSD also were analyzed in Leydig cells that were purified 7 days after endogenous glucocorticoid levels were suppressed by adrenalectomy (ADX). Oxidative activity declined in Leydig cells after ADX (22.53 +/- 1.12 pmol/h.10(6) cells, mean +/- SEM vs. 31.47 +/- 1.48 pmol/.10(6) cells in sham-operated controls, P < 0.05), whereas there was no change in reductive activity. This indicated that physiologically active corticosterone is involved in maintaining the predominance of 11 beta-HSD oxidation. When enzyme activities were analyzed in Leydig cells after 3 days of hormonal treatment in vitro, oxidation and reduction were observed to change in opposing directions. Culture of Leydig cells from sham-operated control rats with either LH, T, or EGF resulted in declines in oxidative activity from 33.35 +/- 0.77 to 28.24 +/- 1.93, 27.30 +/- 0.96, and 24.13 +/- 1.02 pmol/ h.10(6) cells (x +/- SE), respectively. However, EGF stimulated 11 beta-HSD reductive activity in cultured Leydig cells from both control (from 18.97 +/- 1.10 to 27.16 +/- 0.71 pmol/h.10(6) cells and ADX rats (from 16.51 +/- 0.75 to 23.56 +/- 0.84 pmol/h.10(6) cells). Among the hormonal treatments, only DEX increased oxidative activity and simultaneously decreased reductive activity in Leydig cells from ADX rats. This increase accentuated the predominance of oxidative activity in Leydig cells, with a ratio of oxidative to reductive activity of 4:1 after DEX treatment, compared with 2:1 in controls that were untreated. We conclude that 11 beta-HSD activity in Leydig cells is primarily oxidative. Moreover, oxidation and reduction are regulated separately by hormones.
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PMID:Hormonal regulation of oxidative and reductive activities of 11 beta-hydroxysteroid dehydrogenase in rat Leydig cells. 897 99

Antiinflammatory mechanisms are important in ovulation and may be regulated by cortisol (F). We previously showed that after administration of human (h)CG for ovulation induction, luteinized granulosa cells (LGC) abundantly express 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) messenger RNA but not 11betaHSD type 2 (11betaHSD2) messenger RNA. 11ssHSD1 is responsible for the reversible formation of antiinflammatory F from its inactive precursor cortisone (E), whereas 11betaHSD2 unidirectionally converts F to E through 11-oxidation. This pattern of gene expression predicts that LGC from periovulatory follicles would show increased activation of E to F, compared with granulosa cells from immature follicles (IGC), and that follicular fluid concentrations of E and F would alter accordingly. To test this hypothesis, we isolated IGC, thecal cells (TC), and follicular fluid, from ovaries of cyclic women, removed during surgery for benign gynecological disease. LGC and follicular fluid were aspirated from periovulatory follicles, 35 h after hCG injection, in patients undergoing in vitro fertilization treatment. In an 11betaHSD assay based on interconversion of tritiated E and F by cell suspensions in vitro, IGC (% conversion, 0.6 +/- 0.4, mean +/- SEM) and collagenase-dispersed TC (0.2 +/- 0.1%) were unable to convert E to F, whereas LGC (36.3 +/- 3.7%) were highly efficient at this reaction. Immature granulosa cells, LGC, and (to a lesser extent) TC were all able to convert F to E. Correspondingly, follicular fluid concentrations of total F and F:E ratios were significantly higher in periovulatory follicles, compared with immature follicles. Culturing IGC for 48 h in the presence of hFSH resulted in increased 11betaHSD1 reductase activity, paralleling stimulation of estrogen (aromatase activity) and progesterone biosynthesis. Similar treatment with hLH did not influence 11betaHSD1 reductase activity, except in a patient with more mature IGC, which also showed a significant increase in E-to-F conversion, as well as progesterone synthesis in response to hLH. These data confirm that 11betaHSD activity in the human ovary is developmentally regulated and gonadotropin responsive, favoring metabolism of F to E in immature follicles and E to F in periovulatory follicles. Increased formation of F by LGC in periovulatory follicles is consistent with an antiinflammatory function for this glucocorticoid at ovulation.
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PMID:Development-related increase in cortisol biosynthesis by human granulosa cells. 1113 35

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GRalpha and GRbeta) and 11beta-hydroxysteroid dehydrogenase type I (11betaHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GRalpha, GRbeta, and 11betaHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GRalpha and 11betaHSD1 under basal conditions. The apparent K(m) and maximum velocity for the conversion of cortisone to cortisol were 440 +/- 14 nmol/L and 75 +/- 7 pmol/mg protein.h and 437 +/- 16 nmol/L and 33 +/- 6 pmol/mg protein.h (mean +/- SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50-1000 nmol/L) resulted in a dose-dependent decline in GRalpha expression and a dose-dependent increase in GRbeta expression. 11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50-1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GRalpha, GRbeta, and 11betaHSD1 expression is mediated exclusively by the GRalpha ligand-binding variant. In contrast, 11betaHSD1 was down-regulated by insulin (20-100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11betaHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11betaHSD1 activity. Although neither testosterone nor androstenedione (5-200 nmol/L) affected 11betaHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11betaHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GRalpha, GRbeta, and 11betaHSD1 expression by the ligand-binding GRalpha isoform. Additionally, insulin and insulin-like growth factor I regulation of 11betaHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action.
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PMID:Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? 1134 42

Glucocorticoid hormone controls Leydig cell steroidogenic function through a receptor-mediated mechanism. The enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) plays an important role in Leydig cells by metabolizing glucocorticoids, and catalyzing the interconversion of corticosterone (the active form in rodents) and 11-dehydrocorticosterone (the biologically inert form). The net direction of this interconversion determines the amount of biologically active ligand, corticosterone, available for glucocorticoid receptor binding. We hypothesize that 11betaHSD oxidative and reductive activities are controlled separately in Leydig cells, and that shifts in the favored direction of 11betaHSD catalysis provide a mechanism for the control of intracellular corticosterone levels. Therefore, in the present study, we tested the dependency of 11betaHSD oxidative and reductive activities on protein kinase C (PKC) and calcium-dependent signaling pathways. 11betaHSD oxidative and reductive activities were measured in freshly isolated intact rat Leydig cells using 25 nM radiolabeled substrates after treatment with protein kinase modulators. We found that PKC and calcium-dependent signaling had opposing effects on 11betaHSD oxidative and reductive activities. Stimulation of PKC using the PKC activator, 6-[N-decylamino]-4-hydroxymethylinole (DHI), increased 11betaHSD oxidative activity from a conversion rate of 5.08% to 48.23% with an EC50 of 1.70 +/- 0.44 microM (mean +/- SEM), and inhibited reductive activity from 26.90% to 3.66% conversion with an IC50 of 0.22 +/- 0.05 microM. This indicated that PKC activation in Leydig cells favors 11betaHSD oxidation and lower levels of corticosterone. The action of DHI was abolished by the PKC inhibitor bisindolylmaleimide I. In contrast, addition of calcium to Leydig cells increased 11betaHSD reductive activity while decreasing oxidative activity, thereby favoring reduction and conversion of inert 11-dehydrocorticosterone into active corticosterone. The opposite effect was seen after elimination of calcium-dependent signaling, including removal of calcium by EGTA or addition of the calmodulin (calcium binding protein) inhibitor SKF7171A, or the calcium/calmodulin-dependent protein kinase I (CaMK II) inhibitor, KN62. We conclude that 11betaHSD oxidative and reductive activities are separately regulated and that, in contrast to calcium-dependent signaling, PKC stimulates 11betaHSD oxidation while inhibiting 11betaHSD reduction. Maintenance of a predominantly oxidative 11betaHSD could serve to eliminate adverse glucocorticoid-induced action in Leydig cells.
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PMID:Protein kinase C increases 11beta-hydroxysteroid dehydrogenase oxidation and inhibits reduction in rat Leydig cells. 1178 Sep 17

Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11beta-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg.kg-1.day-1 for 7 days) and 11beta-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means +/- SEM; Sham = 105 +/- 8 and CRF = 149 +/- 10 mmHg) and Pcr (Sham = 0.42 +/- 0.03 and CRF = 2.53 +/- 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 +/- 0.26 and CRF = 0.61 +/- 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 +/- 0.090 (before) vs 0.89 +/- 0.09 microEq/min (after) and CRF = 1.05 +/- 0.05 (before) vs 0.37 +/- 0.07 microEq/min (after); P < 0.05). 11beta-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 +/- 0.09 and CRF = 0.217 +/- 0.07 nmol.min-1.mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is maintained during CRF development despite normal Pald levels. This adaptation may be mediated by renal 11beta-HSD2 activity, which, when normalized for GFR, became similar to that of control rats, suggesting that mineralocorticoid receptors maintain their aldosterone selectivity.
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PMID:Role of 11beta-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure. 2002 86

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