11beta Hydroxysteroid Dehydrogenase

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Alex Odermatt - One of the best experts on this subject based on the ideXlab platform.

  • 11beta Hydroxysteroid Dehydrogenase 1 inhibiting constituents from eriobotrya japonica revealed by bioactivity guided isolation and computational approaches
    Bioorganic & Medicinal Chemistry, 2010
    Co-Authors: Judith M Rollinger, Daniela Schuster, Gerhard Wolber, Denise V Kratschmar, Petra H Pfisterer, Christel Gumy, Evelyne M Aubry, Sarah Brandstotter, Hermann Stuppner, Alex Odermatt
    Abstract:

    The inhibition of 11beta-Hydroxysteroid Dehydrogenase 1 (11beta-HSD1), which catalyzes the conversion of inactive 11-ketoglucocorticoids to active 11beta-hydroxyglucocorticoids, emerged as promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes. In this study the leaves of the anti-diabetic medicinal plant loquat (Eriobotrya japonica) were phytochemically investigated following hints from a pharmacophore-based virtual screening and a bioactivity-guided approach. Determination of the 11beta-HSD1 and 11beta-HSD2 inhibitory activities in cell lysates revealed triterpenes from the ursane type as selective, low micro-molar inhibitors of 11beta-HSD1, that is, corosolic acid (1), 3-epicorosolic acid methyl ester (4), 2-alpha hydroxy-3-oxo urs-12-en-28-oic acid (6), tormentic acid methyl ester (8), and ursolic acid (9). Importantly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11beta-HSD1-inhibiting 11-keto-ursolic acid (17) and 3-acetyl-11-keto-ursolic acid (18) a structure-activity relationship was deduced for this group of pentacyclic triterpenes. The mechanism of action elucidated in the present work together with the previously determined pharmacological activities provides these natural products with an astonishing multi-targeted anti-diabetic profile.

  • The glucocorticoid-activating enzyme 11beta-Hydroxysteroid Dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations.
    The Journal of steroid biochemistry and molecular biology, 2010
    Co-Authors: Alex Odermatt, Lyubomir G Nashev
    Abstract:

    The primary function of 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) is to catalyze the conversion of inactive to active glucocorticoid hormones and to modulate local glucocorticoid-dependent gene expression. Thereby 11beta-HSD1 plays a key role in the regulation of metabolic functions and in the adaptation of the organism to energy requiring situations. Importantly, elevated 11beta-HSD1 activity has been associated with metabolic disorders, and recent investigations with rodent models of obesity and type 2 diabetes provided evidence for beneficial effects of 11beta-HSD1 inhibitors, making this enzyme a promising therapeutic target. Several earlier and recent studies, mainly performed in vitro, revealed a relatively broad substrate spectrum of 11beta-HSD1 and suggested that this enzyme has additional functions in the metabolism of some neurosteroids (7-oxy- and 11-oxyandrogens and -progestins) and 7-oxysterols, as well as in the detoxification of various xenobiotics that contain reactive carbonyl groups. While there are many studies on the effect of inhibitors on cortisone reduction and circulating glucocorticoid levels and on the transcriptional regulation of 11beta-HSD1 in obesity and diabetes, only few address the so-called alternative functions of this enzyme. We review recent progress on the biochemical characterization of 11beta-HSD1, with a focus on cofactor and substrate specificity and on possible alternative functions of this enzyme.

  • Diazepane-acetamide derivatives as selective 11beta-Hydroxysteroid Dehydrogenase type 1 inhibitors.
    Expert opinion on therapeutic patents, 2009
    Co-Authors: Alex Odermatt
    Abstract:

    WO2008052638 describes the identification and synthesis of diazepane- acetamide derivatives as a novel class of selective small molecule inhibitors of 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) for the treatment of metabolic syndrome. The generic structure of the disclosed diazepane-acetamide derivatives offers considerable possibilities for modifications that allow optimizing compound properties. Further studies to assess target selectivity, species-specificity, modulation of tissue-specific functions of 11beta-HSD1 as well as interference with alternative functions of this enzyme are needed to explore the therapeutic potential of these chemicals.

  • Selective inhibition of 11beta-Hydroxysteroid Dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid.
    The Journal of steroid biochemistry and molecular biology, 2009
    Co-Authors: Dirk Classen-houben, Alex Odermatt, Daniela Schuster, Thierry Da Cunha, Gerhard Wolber, Ulrich Jordis, Bernhard Kueenburg
    Abstract:

    Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11beta-Hydroxysteroid Dehydrogenase (11beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active 11beta-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11beta-HSD1 and 11beta-HSD2. Here, we compare the biological activity of 18beta-GA and its diastereomer 18alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18alpha-GA selectively inhibits 11beta-HSD1 but not 11beta-HSD2. This is in contrast to 18beta-GA, which preferentially inhibits 11beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11beta-HSD1, we provide an explanation for the differences in the activities of 18alpha-GA and 18beta-GA. This model will be used to design novel selective derivatives of GA.

  • Hexose-6-phosphate Dehydrogenase modulates the effect of inhibitors and alternative substrates of 11beta-Hydroxysteroid Dehydrogenase 1.
    Molecular and cellular endocrinology, 2008
    Co-Authors: Zoltán Balázs, Michael E Baker, Lyubomir G Nashev, Charlie Chandsawangbhuwana, Alex Odermatt
    Abstract:

    Intracellular glucocorticoid reactivation is catalyzed by 11beta-Hydroxysteroid Dehydrogenase 1 (11beta-HSD1), which functions predominantly as a reductase in cells expressing hexose-6-phosphate Dehydrogenase (H6PDH). We recently showed that the ratios of cortisone to cortisol and 7-keto- to 7-hydroxy-neurosteroids are regulated by 11beta-HSD1 and very much depend on coexpression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11beta-HSD1-dependent interconversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11beta-HSD1 or coexpressing 11beta-HSD1 and H6PDH, we observed significant differences of 11beta-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11beta-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells overexpressing 11beta-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11beta-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11beta-HSD1 reductase activity in differentiated THP-1 macrophages (IC(50) 8.1+/-0.9microM). 7-Keto-DHEA but not 7-KC inhibited 11beta-HSD1 in HEK-293 cell lysates. In conclusion, cellular factors such as H6PDH can significantly modulate the effect of inhibitors and alternative 7-oxygenated substrates on intracellular glucocorticoid availability.

Paul M. Stewart - One of the best experts on this subject based on the ideXlab platform.

  • a novel selective 11beta Hydroxysteroid Dehydrogenase type 1 inhibitor prevents human adipogenesis
    Journal of Endocrinology, 2008
    Co-Authors: Iwona J. Bujalska, Laura Gathercole, Jeremy W. Tomlinson, C Darimont, J Ermolieff, Andrea Fanjul, Pa Rejto, Paul M. Stewart
    Abstract:

    Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11beta-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11beta-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 microM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11beta-HSD1 inhibitor PF-877423. 11beta-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11beta-HSD1 oxo-reductase activity (from nil on day 0 to 5.9+/-1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate Dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11beta-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11beta-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.

  • A novel selective 11beta-Hydroxysteroid Dehydrogenase type 1 inhibitor prevents human adipogenesis.
    The Journal of endocrinology, 2008
    Co-Authors: Iwona J. Bujalska, Laura Gathercole, Jeremy W. Tomlinson, C Darimont, J Ermolieff, Andrea Fanjul, Pa Rejto, Paul M. Stewart
    Abstract:

    Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11beta-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11beta-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 microM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11beta-HSD1 inhibitor PF-877423. 11beta-HSD1 mRNA expression increased across adipocyte differentiation (P

  • mechanisms of disease selective inhibition of 11beta Hydroxysteroid Dehydrogenase type 1 as a novel treatment for the metabolic syndrome
    Nature Clinical Practice Endocrinology & Metabolism, 2005
    Co-Authors: Jeremy W. Tomlinson, Paul M. Stewart
    Abstract:

    The magnitude of the obesity and metabolic syndrome epidemic has heightened the need for the development of new and effective treatments. Although circulating cortisol concentrations are not elevated in obesity or in the metabolic syndrome, decreasing the tissue-specific generation of cortisol through inhibition of 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) has been postulated as a therapeutic strategy. Observations in cohorts of obese patients, in comparison with those with type 2 diabetes, have suggested that the ability to decrease tissue-specific cortisol production might represent a protective mechanism to improve insulin sensitivity and prevent diabetes. In rodents, pharmacologic exploitation of this mechanism, through the development of inhibitors selective for 11beta-HSD1 (in preference to the type 2 isoform), dramatically improves insulin sensitivity. Here we review the published data and the rationale for treatment in humans, as well as discussing potential problems and adverse effects of future selective 11beta-HSD1 inhibitors.

  • weight loss increases 11beta Hydroxysteroid Dehydrogenase type 1 expression in human adipose tissue
    The Journal of Clinical Endocrinology and Metabolism, 2004
    Co-Authors: Jeremy W. Tomlinson, Jasbir S Moore, Penny Clark, Geoff Holder, Lynette Shakespeare, Paul M. Stewart
    Abstract:

    The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-Hydroxysteroid Dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11betaHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All patients achieved significant weight loss (14.1 +/- 1.3% of initial body weight). Total fat mass fell from 41.8 +/- 1.9 to 32.0 +/- 1.7 kg (P < 0.0001). In addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001) and systolic blood pressure and total cholesterol also fell [systolic blood pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total cholesterol, 5.4 +/- 0.2 to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum cortisol/cortisone ratio increased after weight loss (P < 0.01). 11betaHSD1 mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and expression in obesity may act as a compensatory mechanism to enhance insulin sensitivity through a reduction in tissue-specific cortisol concentrations. Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.

  • The functional consequences of 11beta-Hydroxysteroid Dehydrogenase expression in adipose tissue.
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2002
    Co-Authors: Jeremy W. Tomlinson, Paul M. Stewart
    Abstract:

    Clinical observations have highlighted the link between glucocorticoids and obesity. While exogenous glucocorticoids in excess predispose to the development of central obesity, we have focused on cortisol metabolism within human adipose tissue. 11beta-Hydroxysteroid Dehydrogenase (11beta-HSD) inter-converts the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1, the only isoform expressed in adipose tissue, acts predominantly as an oxoreductase to generate cortisol. Expression is higher in omental compared to subcutaneous preadipocytes and activity and expression are potently regulated by growth factors and cytokines. Mice over-expressing 11beta-HSD1 specifically within adipocytes develop central obesity. However, the situation is less clear in humans. Globally, there appears to be inhibition of the enzyme, but expression in human obesity is still not fully characterized; its functional role in adipocyte biology remains to be elucidated. In vitro, 11beta-HSD1 appears to function in promoting adipocyte differentiation and limiting preadipocyte proliferation, but the impact of these effects in vivo upon the regulation of fat mass remains to be defined. Clinical studies utilizing selective 11beta-HSD1 inhibitors may help to answer this question.

Jonathan R Seckl - One of the best experts on this subject based on the ideXlab platform.

  • The role and regulation of 11beta-Hydroxysteroid Dehydrogenase type 1 in the inflammatory response.
    Molecular and cellular endocrinology, 2008
    Co-Authors: Karen E Chapman, James S Gilmour, Agnes E Coutinho, John S Savill, Mohini Gray, Jonathan R Seckl
    Abstract:

    Cortisone, a glucocorticoid hormone, was first used to treat rheumatoid arthritis in humans in the late 1940s, for which Hench, Reichstein and Kendall were awarded a Nobel Prize in 1950 and which led to the discovery of the anti-inflammatory effects of glucocorticoids. To be effective, the intrinsically inert cortisone must be converted to the active glucocorticoid, cortisol, by the intracellular action of 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1). Whilst orally administered cortisone is rapidly converted to the active hormone, cortisol, by first pass metabolism in the liver, recent work has highlighted an anti-inflammatory role for 11beta-HSD1 within specific tissues, including in leukocytes. Here, we review recent evidence pertaining to the anti-inflammatory role of 11beta-HSD1 and describe how inhibition of 11beta-HSD1, as widely proposed for treatment of metabolic disease, may impact upon inflammation. Finally, the mechanisms that regulate 11beta-HSD1 transcription will be discussed.

  • Inhibition of 11beta-Hydroxysteroid Dehydrogenase type 1 as a promising therapeutic target.
    Drug discovery today, 2007
    Co-Authors: Malgorzata Wamil, Jonathan R Seckl
    Abstract:

    Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11beta-HSD1 in adipose tissue. Transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11beta-HSD1 knockout mice have a 'cardioprotective' phenotype, whose effects are also seen with 11beta-HSD1 inhibitors in rodents. However, any major metabolic effects of 11beta-HSD1 inhibition in humans are, as yet, unreported. 11beta-HSD1 null mice also resist cognitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11beta-HSD1 inhibition is an emerging pleiotropic therapeutic target.

  • 11beta-Hydroxysteroid Dehydrogenase type 1--a role in inflammation?
    Molecular and cellular endocrinology, 2006
    Co-Authors: Karen E Chapman, James S Gilmour, Agnes E Coutinho, John S Savill, Jonathan R Seckl
    Abstract:

    Glucocorticoids are widely used for their potent anti-inflammatory effects. Endogenous glucocorticoids are immunomodulatory and shape both adaptive and innate immune responses. Over the past decade, it has become apparent that an important level of control over endogenous glucocorticoid action is exerted by the 11beta-Hydroxysteroid Dehydrogenase enzymes. The type 1 enzyme, 11beta-HSD1, reduces inert glucocorticoids into active forms, thereby increasing intracellular ligand availability to receptors. Although 11beta-HSD1 activity has been shown to play an important role in the metabolic actions of glucocorticoids, its role in the immune response has, until recently, remained unclear. Here we review recent evidence pertaining to the role of 11beta-HSD1 in the inflammatory response.

  • Ontogeny of 11beta-Hydroxysteroid Dehydrogenase: activity in the placenta, kidney, colon of fetal rats and rabbits.
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2001
    Co-Authors: S. Hundertmark, H. Bühler, M. Fromm, B Kruner-gareis, M Kruner, V. Ragosch, K Kuhlmann, Jonathan R Seckl
    Abstract:

    Mechanisms to regulate closely fetal GC exposure are of considerable importance, as certain organs (kidney, brain) are adversely affected by excess GCs. 11beta-Hydroxysteroid Dehydrogenase type 2 (11beta-HSD2) reduces transplacental passage of maternal GCs to the fetus. We hypothesized that 11beta-HSD2, if active in fetal kidney and colon, might allow local tissue modulation of GC access during the critical last trimester. We determined the presence, ontogeny and functionality of 11beta-HSD in the placenta and fetal, neonatal and adult kidney and colon in rats and rabbits and the cortisol:cortisone ratio in human amniotic fluid, which represents fetal urine. There was clear a 11beta-HSD2 expression in last trimester fetal colon, kidney and placenta in both rats and rabbits. This appeared of functional importance, since the potency of cortisol on fetal rabbit colonic sodium flux in the Ussing chamber was increased by 11beta-HSD inhibition. In human amniotic fluid, we found a decreasing ratio of cortisol:cortisone across the last trimester, suggesting an analogous onset of renal 11beta-HSD2 activity in the human fetal kidney. Local fetal tissue 11beta-HSD2 may modulate exposure to the deleterious effects of GCs upon target tissue maturation during sensitive periods of late gestation when fetal GC levels rise to prepare other organs (lung) for adaptations at birth.

  • 11beta-Hydroxysteroid Dehydrogenase type 2 in the rat corpus luteum: induction of messenger ribonucleic acid expression and bioactivity coincident with luteal regression.
    Endocrinology, 1996
    Co-Authors: Brendan J. Waddell, Rafn Benediktsson, Jonathan R Seckl
    Abstract:

    The corpus luteum (CL) is the major source of progesterone during rat pregnancy, and its regression precedes and is essential for parturition. Recent studies show that luteal regression in the rat can be blocked by the administration of synthetic glucocorticoids, yet endogenous glucocorticoids are maximal at the time of normal luteal regression in pregnancy. This suggests that endogenous glucocorticoid may be inactivated locally within the CL, presumably via the enzyme 11beta-Hydroxysteroid Dehydrogenase type 2 (11beta-HSD-2), which is known to regulate glucocorticoid access to receptors in other target tissues. This possibility was examined in the present study by measurement of 11beta-HSD-2 messenger RNA (mRNA) expression and bioactivity in rat CL over the second half of pregnancy, thus covering periods of maximal and minimal progesterone secretion. 11beta-HSD-2 bioactivity was measured in luteal homogenates obtained from rats on days 11, 16, 19, and 22 of pregnancy (term = day 23). Bioactivity was meas...

Jirí Pácha - One of the best experts on this subject based on the ideXlab platform.

  • Cloning of chicken 11beta-Hydroxysteroid Dehydrogenase type 1 and its tissue distribution.
    The Journal of steroid biochemistry and molecular biology, 2008
    Co-Authors: Petra Klusonová, Ivan Miksík, Marek Kucka, Peter Ergang, Jana Bryndová, Jirí Pácha
    Abstract:

    11beta-Hydroxysteroid Dehydrogenase type 1 (11HSD1) is an enzyme that interconverts active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inactive 11-oxo derivatives (cortisone, 11-dehydrocorticosterone). Although bidirectional, it is considered to operate in vivo as an 11-reductase that regenerates active glucocorticoids and thus amplifies their local activity in mammals. Here we report the cloning, characterization and tissue distribution of chicken 11HSD1 (ch11HSD1). Its cDNA predicts a protein of 300 amino acids that share 51-56% sequence identity with known mammalian 11HSD1 proteins, while in contrast to most mammals, ch11HSD1 contains only one N-linked glycosylation site. Analysis of the tissue distribution pattern by RT-PCR revealed that ch11HSD1 is expressed in a large variety of tissues, with high expression in the liver, kidney and intestine, and weak in the gonads, brain and heart. 11-Reductase activity has been found in the liver, kidney, intestine and gonads with low or almost zero activity in the brain and heart. These results provide evidence for a role of 11HSD1 as a tissue-specific regulator of glucocorticoid action in non-mammalian vertebrates and may serve as a suitable model for further analysis of 11HSD1 evolution in vertebrates.

  • 11beta-Hydroxysteroid Dehydrogenase in the heart of normotensive and hypertensive rats.
    The Journal of steroid biochemistry and molecular biology, 2005
    Co-Authors: Karla Mazancová, Martin Kopecký, Ivan Miksík, Jirí Pácha
    Abstract:

    Corticosteroids have been shown to play a role in cardiac remodeling, with the possibility of a direct effect of overexpression of 11beta-Hydroxysteroid Dehydrogenase (11HSD) isoform 2 at the level of the cardiomyocytes. The aim of this study was to examine cardiac steroid metabolism in hypertensive rats with hearts that are hypertrophied and fibrotic and have structural alterations in the coronary circulation. To assess possible alterations of cardiac steroid metabolism the expression and activity of both isoforms of 11beta-Hydroxysteroid Dehydrogenase (11HSD) were studied in spontaneously hypertensive rats (SHR), their normotensive controls Wistar-Kyoto (WKY), and in Dahl salt-sensitive (DS) and salt-resistant rats (DR) kept on a low- or high-salt diet. Using real-time quantitative RT-PCR and enzyme activity assay we found strain-dependent differences in cardiac metabolism of glucocorticoids. In Dahl rats expression of 11HSD1 and 11HSD2 mRNA was lower in DS than in DR rats and was not influenced by dietary salt intake; 11HSD1 mRNA was expressed at higher level than 11HSD2 mRNA. NADP(+)-dependent cardiac 11HSD activity showed similar distribution as 11HSD1 mRNA-lower activity in DS than in DR rats and no effect of salt intake. In SHR and WKY strains 11HSD2 mRNA expression was significantly higher in WKY than in SHR but no differences were observed in 11HSD1 mRNA abundance and NADP(+)-dependent 11HSD activity. These results show that the heart is able to metabolize glucocorticoids and that this metabolism is strain-dependent but do not support the notion of association between cardiac hypertrophy and changes of 11HSD1 and 11HSD2 expression.

  • Placental 11beta-Hydroxysteroid Dehydrogenase in Dahl and spontaneously hypertensive rats.
    American journal of hypertension, 2003
    Co-Authors: Karla Mazancová, Ivan Miksík, Jaroslav Kunes, Jirí Pácha
    Abstract:

    Studies in normotensive rats showed that excessive fetal exposure to maternal glucocorticoids retards growth and programs hypertension in later life. This excessive exposure is proposed to occur due to a reduction of the placental barrier to maternal glucocorticoids that is provided by 11beta-Hydroxysteroid Dehydrogenase (11betaHSD). To assess the possible alterations of glucocorticoid placental barrier in two genetic models of hypertension - spontaneously hypertensive (SHR) and Dahl salt-sensitive rats (DS) and their normotensive counterparts Wistar-Kyoto (WKY) and Dahl salt-resistant rats (DR)-we performed real-time reverse transcriptase-polymerase chain reaction analysis and bioactivity measurements of placental 11betaHSD in the last third of gestation. Whereas 11betaHSD2 mRNA expression was not different among the investigated strains, 11betaHSD1 mRNA abundance was 2.4 times higher in WKY than in SHR and 9.6 times higher in DS than in DR placentae. The 11betaHSD2 activity studies performed in placental homogenates revealed activity that did not differ among the strains. Concomitant with 11betaHSD1 mRNA expression 11-oxoreductase activity was clearly evident in all strains and was higher in WKY and DS rats than in SHR and DR, respectively. Nevertheless, the net 11betaHSD activity of tissue fragments (11beta-Dehydrogenase minus 11-oxoreductase) was tended toward Dehydrogenase action, ie, toward corticosterone inactivation and was significantly lower in DS than in DR rats. The 11beta-Dehydrogenase/11-oxoreductase ratio was less than 2:1 in SHR and WKY rats, whereas this ratio was 9:1 in DR and 4.5:1 in DS rats. These data suggest that the placental glucocorticoid barrier is not decreased in SHR rats in comparison with normotensive WKY but is lower in DS than in DR counterparts. It cannot be excluded, therefore, that the placental glucocorticoid barrier in Dahl rats influences the pathways that might lead to the sensitivity of blood pressure to high salt intake in later life.

E Maser - One of the best experts on this subject based on the ideXlab platform.

  • 11beta-Hydroxysteroid Dehydrogenase type 1: purification from human liver and characterization as carbonyl reductase of xenobiotics.
    Molecular and cellular endocrinology, 2005
    Co-Authors: E Maser, V Wsol, H-j Martin
    Abstract:

    11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD1) catalyzes the interconversion of 11-oxo glucocorticoids to their 11-hydroxy metabolites, thereby controlling access of glucocorticoid hormones to the glucocorticoid receptor. Interestingly, evidence is emerging that 11beta-HSD1 fulfills an additional role in the metabolism of xenobiotic carbonyl compounds. In our studies, 11beta-HSD1 was identified as a microsomal reductase that initiates the final detoxification of xenobiotics by reducing them to alcohols that are easier to conjugate and eliminate. With its pluripotent substrate specificities for glucocorticoids and xenobiotics, 11beta-HSD1 adds to an expanding list of those Hydroxysteroid Dehydrogenases which, on the one hand, are capable of catalyzing the carbonyl reduction of non-steroidal carbonyl compounds, and which, on the other hand, exhibit great specificity to their physiological steroid substrates. It is conceivable that large interferences must occur between endogenous steroid metabolism and the detoxification of xenobiotic compounds on the level of Hydroxysteroid Dehydrogenases.

  • Human 11beta-Hydroxysteroid Dehydrogenase 1/carbonyl reductase: additional domains for membrane attachment?
    Chemico-biological interactions, 2001
    Co-Authors: A Blum, A Raum, H Martin, E Maser
    Abstract:

    11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD 1) is a membrane integrated glycoprotein, which physiologically performs the interconversion of active and inactive glucocorticoid hormones and which also participates in xenobiotic carbonyl compound detoxification. Since 11beta-HSD 1 is fixed to the endoplasmic reticulum (ER) with a N-terminal membrane spanning domain, the enzyme is very difficult to purify in an active state. Upon expression experiments in Escherichia coli, 11beta-HSD 1 turns out to be hardly soluble without detergents. This study describes attempts to increase the solubility of 11beta-HSD 1 via mutagenesis experiments by generating several truncated forms expressed in E. coli and the yeast Pichia pastoris. Furthermore, we investigated if the codon for methionine 31 in human 11beta-HSD 1 could serve as an alternative start codon, thereby leading to a soluble form of the enzyme, which lacks the membrane spanning segment. Our results show that deletion of the hydrophobic membrane spanning domain did not alter the solubility of the enzyme. In contrast, the enzyme remained bound to the ER membrane even without the N-terminal membrane anchor. However, activity could not be found, neither with the truncated protein expressed in E. coli nor with that expressed in P. pastoris. Hydrophobicity plots proved the hydrophobic nature of 11beta-HSD 1 and indicated the existence of additional membrane attachment sites within its primary structure.

  • Heterogeneity of 11beta-Hydroxysteroid Dehydrogenase type 1/microsomal carbonyl reductase (11beta-HSD/CR) in guinea pig tissues. Purification of the liver form suggests modification in the cosubstrate binding site.
    Toxicology, 2000
    Co-Authors: U C Oppermann, G Nagel, E Möbus, E Maser
    Abstract:

    11beta-Hydroxysteroid Dehydrogenase (11beta-HSD) and xenobiotic carbonyl reductase activities were determined in guinea pig tissue microsomes. The data indicate the presence of a NADP(H) dependent form, distinct from the known type I isozyme. Purification of 11beta-HSD-1 from liver microsomes resulted in two distinct peaks, resolved by dye-ligand chromatography, indicating differences in the cosubstrate binding site. Immunoblot analysis using anti 11beta-HSD-1 antibodies reveals the presence of similar structural determinants between the enzyme forms. Both have an apparent molecular mass of 32 kDa, suggesting protein modifications occurring in the type 1 isozyme which account for the differences in chromatographic behaviour.

  • Interindividual variability in the expression and NNK carbonyl reductase activity of 11beta-Hydroxysteroid Dehydrogenase 1 in human lung.
    Cancer letters, 1999
    Co-Authors: M Soldan, G Nagel, M Losekam, M Ernst, E Maser
    Abstract:

    The balance between metabolic activation and detoxification is critical in determining the susceptibility to lung cancer upon exposure to the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Carbonyl reduction of NNK, followed by glucuronidation, is the main detoxification pathway of this lung carcinogen in humans. Recently, we have identified 11beta-Hydroxysteroid Dehydrogenase type 1 (11beta-HSD 1) as microsomal NNK carbonyl reductase in liver and lung. In the present study, the interindividual variability of 11beta-HSD 1 expression and NNK-carbonyl reductase activity was examined in human lung by RT-PCR, Western blot analysis and enzyme activity. Levels of 11beta-HSD 1 mRNA varied over an almost 20-fold range among different subjects. Levels of NNK carbonyl reductase activity in lung microsomes closely resembled the relative amounts of immunoreactive protein as determined by Western blot analysis. In view of the large interindividual differences in the susceptibility of tobacco smoke related lung cancer, we present the first data on the variability of 11beta-HSD 1 expression and NNK carbonyl reduction in human lung.