Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A rapid screening assay for chemicals inhibiting 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11beta-HSD activities. Inhibition of 11beta-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC50 6.3 microM). Abietic acid inhibited both 11beta-HSD1 (IC50 27 microM for reduction and 2.8 microM for oxidation) and 11beta-HSD2 (IC50 12 microM). Our results demonstrate for the first time that flavanone selectively inhibits 11beta-HSD1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2'-hydroxyflavanone efficiently inhibited reductive (IC50 18 and 10 microM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11beta-HSD1 and did not inhibit 11beta-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11beta-HSD1 and 11beta-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo.
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PMID:A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11beta-HSD1 reductase activity. 1465 49

Two isozymes of the 11beta-hydroxysteroid dehydrogenase (11-HSD) are responsible for the interconversion of cortisol (F) and cortisone (E). The type 1 isozyme, 11-HSD1, acts mainly as a reductase in vivo, activating E to F, whereas the type 2, 11-HSD2, acts as a dehydrogenase, inactivating F to E. 11-HSD1 is the most abundant in the liver and 11-HSD2 in the kidney. In this study, we attempted to determine which isozyme and organs primarily contribute to equilibrium of plasma F and E concentrations in the peripheral circulation and to clarify differences in 11-HSD activities among adrenocortical disorders. Upon selective catheterizations for adrenocortical and renovascular disorders, plasma F and E concentrations in the femoral vein were closer to those in the renal vein than those in the hepatic vein. Values for mean plasma F/E ratios in the peripheral vein were in-between those of the adrenal and renal veins. A double reciprocal plot between peripheral plasma F and E concentrations in patients with various adrenocortical tumors was almost identical to that in normal subjects. Mean plasma F/E ratio in peripheral blood was higher in patients with Cushing's syndrome and was lower in patients with primary aldosteronism and nonfunctioning adrenocortical adenoma than that in normal subjects. These results suggest that renal 11-HSD2 is a main factor controlling the equilibrium of plasma F and E concentrations in the periphery and that cortisol and aldosterone excess do not change the equilibrium of plasma F and E concentrations in the peripheral circulation, but may alter expression of 11-HSD2. Alternation of 11-HSD2 activities as well as corticosteroid levels may be important in the pathophysiology of adrenocortical disorders.
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PMID:Plasma cortisol and cortisone concentrations in normal subjects and patients with adrenocortical disorders. 1468 48

Glucocorticoids (GCs) exert potent, but poorly characterized, effects on the skeleton. The cellular activity of GCs is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). The type 1 isoform, which predominates in bone, functions as a reductase in intact cells and regenerates active cortisol (corticosterone) from circulating inert 11-keto forms. The aim of the present study was to investigate the role of this intracrine activation of GCs on normal bone physiology in vivo using mice deficient in 11betaHSD1 (HSD1(-/-)). The HSD1(-/-) mice exhibited no significant changes in cortical or trabecular bone mass compared with wild-type (Wt) mice. Aged HSD1(-/-) mice showed age-related bone loss similar to that observed in Wt mice. Histomorphometric analysis showed similar bone formation and bone resorption parameters in HSD1(-/-) and Wt mice. However, examination of bone marrow composition revealed a total absence of marrow adipocytes in HSD1(-/-) mice. Cells from Wt and HSD1(-/-) mice exhibited similar growth rates as well as similar levels of production of osteoblastic markers. The adipocyte-forming capacity of in vitro cultured bone marrow stromal cells and trabecular osteoblasts was similar in HSD1(-/-) and Wt mice. In conclusion, our results suggest that 11betaHSD1 amplification of intracellular GC actions in mice may be required for bone marrow adipocyte formation, but not for bone formation. The clinical relevance of this observation remains to be determined.
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PMID:Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation. 1471 14

11 Beta-hydroxysteroid dehydrogenases type 1 and 2 (11 beta-HSD1 and 11 beta-HSD2) are microsomal enzymes responsible for the interconversion of cortisol into the inactive form cortisone and vice versa. 11 beta-HSD1 is mainly present in the liver, and has predominantly reductase activity although its function has not yet been elucidated. 11 beta-HSD2, present in mineralocorticoid target tissues such as the kidney, converts cortisol into cortisone. Reduced activity due to inhibition or mutations of 11 beta-HSD2 leads to hypertension and hypokalemia resulting in the Apparent Mineralocorticoid Excess Syndrome (AMES). Like humans, cats are highly susceptible for hypertension. As large species differences exist with respect to the kinetic parameters (K(m) and V(max)) and amino acid sequences of both enzymes, we determined these characteristics in the cat. Both enzyme types were found in the kidneys. 11 beta-HSD1 in the feline kidney showed bidirectional activity with predominantly dehydrogenase activity (dehydrogenase: K(m) 1959+/-797 nM, V(max) 766+/-88 pmol/mg*min; reductase: K(m) 778+/-136 nM, V(max) 112+/-4 pmol/mg*min). 11 beta-HSD2 represents a unidirectional dehydrogenase with a higher substrate affinity (K(m) 184+/-24 nM, V(max) 74+/-3 pmol/mg*min). In the liver, only 11 beta-HSD1 is detected exerting reductase activity (K(m) 10462 nM, V(max) 840 pmol/mg*min). Sequence analysis of conserved parts of 11 beta-HSD1 and 11 beta-HSD2 revealed the highest homology of the feline enzymes with the correspondent enzymes found in man. This suggests that the cat may serve as a suitable model species for studies directed to the pathogenesis and treatment of human diseases like AMES and hypertension.
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PMID:Characterisation of 11 beta-hydroxysteroid dehydrogenases in feline kidney and liver. 1473 82

Glucocorticoids are metabolized by isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There is some controversy concerning the bile acid, chenodeoxycholic acid (CDCA), as a potential endogenously produced inhibitor of 11beta-HSD. The present experiments were designed to determine the relative specificity of CDCA for both isoforms of 11beta-HSD and to assess the biological relevance of inhibition in vascular tissue. IC(50) values (concentrations which inhibit 50% of the enzyme reaction) were calculated using rat liver microsomes as a source of 11beta-HSD1 dehydrogenase, Leydig cells for 11beta-HSD1 dehydrogenase and reductase, aorta for 11beta-HSD1 dehydrogenase and reductase, and sheep kidney for 11beta-HSD2 dehydrogenase. In each case, CDCA functioned as a potent inhibitor of 11beta-HSD1 dehydrogenase with IC(50) values of ranging from 0.2 to 7 micromol/L in contrast to 37 to 200 micromol/L for 11beta-HSD1 reductase. CDCA exhibited relatively weak inhibitory activity against 11beta-HSD2 from sheep kidney with an IC(50) of 70 micromol/L. The effect of CDCA on vascular contraction was studied in aortic rings isolated from Spague-Dawley rats incubated in medium containing corticosterone 10 nmol/L +/- CDCA (1 micromol/L) for 24 hours. Rings were stimulated with graded concentrations of phenylephrine (PE) (10 nmol/L, 100 nmol/L, and 1 micromol/L). Rings exposed to corticosterone and CDCA consistently demonstrated a greater contractile response at lower doses of PE (63% at PE 10 nmol/L, P <.001; 20% at PE 100 nmol/L, P <.025; and 10% at PE 1 micromol/L, not significant [NS]) compared to control preparations incubated with cortiosterone alone. These studies demonstrate (1) that CDCA preferentially affects 11beta-HSD1 dehydrogenase; (2) CDCA does inhibit 11beta-HSD2 dehydrogenase and 11beta-HSD1 reductase but only at high(er) concentrations exceeding 70 micromol/L and 37 micromol/L, respectively; and (3) inhibition of 11beta-HSD1 dehydrogenase in aortic rings by CDCA (1 micromol/L) enhances the contractile response of corticosterone plus PE.
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PMID:Effect of chenodeoxycholic acid on 11beta-hydroxysteroid dehydrogenase in various target tissues. 1516 34

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
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PMID:11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. 1546 42

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11beta-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11beta-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4(+), CD8(+), and B220(+) lymphocytes, as well as CD11c(+) dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4(+) T cells increased their 11beta-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4(+) T cells isolated from aged donors (>16 mo) had increased 11beta-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4(+) T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Ralpha and GCS-induced leucine zipper gene expression. The presence of a functional 11beta-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11beta-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.
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PMID:The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. 1563 10

Corticosterone (CORT) suppresses Leydig cell steroidogenesis by inhibiting the expression of proteins involved in testosterone biosynthesis including steroidogenic acute regulatory protein and steroidogenic enzymes. In most cells, intracellular glucocorticoid levels are controlled by either or both of the two known isoforms of 11beta-hydroxysteroid dehydrogenase (11beta HSD): the nicotinamide adenine dinucleotide phosphate reduced-dependent low-affinity type I 11beta HSD (11beta HSD1) oxidoreductase and the nicotinamide adenine dinucleotide-dependent 11beta HSD2 high-affinity unidirectional oxidase. In Leydig cells, 11beta HSD1 alone may not be sufficient to prevent glucocorticoid-mediated suppression due to its low affinity for CORT at basal concentrations. The high-affinity unidirectional 11beta HSD2, if also present, may be critical for lowering intracellular CORT levels. In the present study, we showed that 11beta HSD2 is present in rat Leydig cells by PCR amplification, immunohistochemical staining, enzyme histochemistry, immunoprecipitation, and Western blotting. Real-time PCR showed a 6-fold enrichment of 11beta HSD2 mRNA in these cells, compared with whole testis and that the amount of 11beta HSD2 message was about 1000-fold lower, compared with 11beta HSD1. Diffuse immunofluorescent staining of 11beta HSD2 protein in the Leydig cell cytoplasm was consistent with its localization in the smooth endoplasm reticulum. 11beta HSD1 or 11beta HSD2 activities were selectively inhibited using antisense methodology: inhibition of 11beta HSD1 lowered reductase activity by 60% and oxidation by 25%, whereas inhibition of 11beta HSD2 alone suppressed oxidase activity by 50%. This shows that the high-affinity, low-capacity 11beta HSD2 isoform, present at only one thousandth the level of the low-affinity isoform may significantly affect the level of CORT. The inhibition of either 11beta HSD1 or 11beta HSD2 significantly lowered testosterone production in the presence of CORT. These data suggest that both types I and II 11beta HSD in Leydig cells play a protective role, opposing the adverse effects of excessive CORT on testosterone production.
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PMID:11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate. 1576 Oct 36

Hexose-6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11beta-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11beta-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11beta-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11beta-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11beta-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.
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PMID:Minireview: hexose-6-phosphate dehydrogenase and redox control of 11{beta}-hydroxysteroid dehydrogenase type 1 activity. 1577 58

Glucocorticoids (GCs) exert powerful anti-inflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Immature DCs demonstrate selective enhancement of 11beta-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11beta-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation.
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PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. 1594 7


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