11-Beta Hydroxysteroid Dehydrogenase

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

  • 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:

    Isoenzymes of 11[beta]-Hydroxysteroid Dehydrogenase affect the tissue-specific interconversion of cortisone and cortisol. In rodents, selective inhibitors of these enzymes improve insulin sensitivity, and we await clinical trials to test whether such drugs can be “magic bullets” to treat type 2 diabetes and the metabolic syndrome.

  • 11 beta Hydroxysteroid Dehydrogenase
    Vitamins and Hormones Series, 1999
    Co-Authors: Paul M. Stewart, Zygmunt S Krozowski
    Abstract:

    In mammalian tissues, at least two isozymes of 11 beta-Hydroxysteroid Dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent Dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid. By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression.

  • urinary free cortisone and the assessment of 11 beta Hydroxysteroid Dehydrogenase activity in man
    Clinical Endocrinology, 1996
    Co-Authors: Mario Palermo, Cedrich L Shackleton, Franco Mantero, Paul M. Stewart
    Abstract:

    OBJECTIVE Two isoforms of 11 beta-Hydroxysteroid Dehydrogenase (11 beta-HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11 beta-HSD2 isoform result in hypertension. The kidney, expressing high levels of 11 beta-HSD2, is the principal source of cortisone in man. We have validated the measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pitultary-adrenal axis in an attempt to more accurately measure the activity of 11 beta-HSD2 in vivo. SUBJECTS Forty-one normal adults, 12 normal children < 12 years of age, 15 patients with Cushing's syndrome, 12 with hypopitultarism on replacement hydrocortisone, 12 with the syndrome of apparent mineralocorticoid excess (AME) and 7 volunteers consuming liquorice. MEASUREMENTS A complete 24-hour urine collection was analysed by gas chromatography/mass spectrometry for "A-ring' reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo-THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol (UFF) and urinary free cortisone were quantified using deuterium-labelled internal standards. RESULTS In normal adults and children, UFE excretion exceeded that of UFF (UFF 30.4 +/- 2.4 micrograms/24h (mean +/- SE), UFE 54.6 +/- 4.1 micrograms/24h, adults) (for conversion to nmol/24h multiply E by 2.78 and F by 2.76 respectively). Thus the normal UFF/UFE ratio was 0.54 +/- 0.05 in contrast to the (THF + allo-THF)/THE ratio of 1.21 +/- 0.06. UFE excretion was normal in hypopituitary patients on replacement hydrocortisone. Although UFE was elevated in all forms of Cushing's syndrome, the UFF/UFE ratio was grossly elevated in patients with the ectopic ACTH syndrome (14.0 +/- 6.7, n = 6). UFE was below the lower limit of the assay (< 1 microgram/24h) in most patients with the so-called type 1 variant of AME and significantly reduced in 4 patients described as having the type 2 variant of AME (10.5 +/- 3.5 micrograms/h, P < 0.05) and in 7 volunteers consuming liquorice (26.8 +/- 10.0 micrograms/24h, P < 0.01). In ectopic ACTH syndrome, AME, and liquorice ingestion the UFF/UFE ratio was more deranged than the (THF + allo-THF)/THE ratio. CONCLUSION In normals the discrepant THF + allo-THF/ THE and UFF/UFE ratio suggests that much more of the UFE is derived from the kidney. Reduction in UFE excretion is seen following liquorice ingestion and in both variants of AME, though it is more profound in AME1. The high UFF/UFE ratio in the mineralocorticoid excess state seen in the ectopic ACTH syndrome is compatible with substrate-saturation of renal 11 beta-HSD2. The measurement of UFE and the UFF/UFE ratio is a significant advance in the analysis of human 11 beta-HSD activity in vivo; in particular, the UFF/UFE ratio appears to be a more sensitive index than the (THF + allo-THF)/THE ratio of renal 11 beta-HSD2 activity.

  • type 2 11 beta Hydroxysteroid Dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes its relationship to birth weight and putative role in fetal adrenal steroidogenesis
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Paul M. Stewart, F M Rogerson, J I Mason
    Abstract:

    Two isoforms of 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) have been described which catalyze the interconversion of cortisol (F) to cortisone (E). 11 beta HSD activity has previously been reported in placenta and fetal membranes, where its role may be to protect the developing fetus from glucocorticoid excess. Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported. We have characterized the isoforms of 11 beta HSD in human fetal membranes and dissected placental tissue at term and investigated the relationship between placental 11 beta HSD activity and fetal and placental weights. 11 beta HSD activity studies in the presence of 0.1 mumol/L F and NAD (indicative of type 2 isoform activity) revealed high levels of activity in trophoblast dissected free of vessels (561 +/- 87 pmol E/h.mg protein; n = 4) > undissected placenta > cotyledenous vessels dissected away from trophoblast > placental and...

  • type 2 11 beta Hydroxysteroid Dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes its relationship to birth weight and putative role in fetal adrenal steroidogenesis
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Paul M. Stewart, F M Rogerson, J I Mason
    Abstract:

    Two isoforms of 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) have been described which catalyze the interconversion of cortisol (F) to cortisone (E). 11 beta HSD activity has previously been reported in placenta and fetal membranes, where its role may be to protect the developing fetus from glucocorticoid excess. Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported. We have characterized the isoforms of 11 beta HSD in human fetal membranes and dissected placental tissue at term and investigated the relationship between placental 11 beta HSD activity and fetal and placental weights. 11 beta HSD activity studies in the presence of 0.1 mumol/L F and NAD (indicative of type 2 isoform activity) revealed high levels of activity in trophoblast dissected free of vessels (561 +/- 87 pmol E/h.mg protein; n = 4) > undissected placenta > cotyledenous vessels dissected away from trophoblast > placental and reflected amnion. In contrast, in the presence of 2.5 mumol/L F and NADP (indicative of type 1 isoform activity), only decidua and chorion demonstrated significant levels of 11 beta HSD activity. Type 1 11 beta HSD activity in chorion was probably due to decidual contamination, in that it was absent in decidua-free fused chorion obtained from a twin pregnancy. In keeping with these data, type 1 11 beta HSD messenger ribonucleic acid (1.5 kilobases) was detected in decidua, but in no other tissue, and high levels of type 2 11 beta HSD messenger ribonucleic acid (1.9 kilobases) were found in undissected placenta and trophoblast. In 27 term placentas, 11 beta HSD activity varied from 194-448 pmol E/h.mg protein. There was a weak, but significant, positive correlation between term placental 11 beta HSD activity and fetal weight (r = 0.408; P = 0.034), but no correlation with placental weight. Thus, in man, the reported association of a small fetus and a large placenta predisposing to adult hypertension cannot be explained on the basis of defective 11 beta HSD activity. However, the placenta offers an immense reservoir for F clearance (1.73-7.95 mumol/min.placenta) and may be a principal factor driving fetal ACTH secretion and, hence, fetal adrenal steroidogenesis.

Brian R Walker - One of the best experts on this subject based on the ideXlab platform.

  • functional effects of polymorphisms in the human gene encoding 11 beta Hydroxysteroid Dehydrogenase type 1 11 beta hsd1 a sequence variant at the translation start of 11 beta hsd1 alters enzyme levels
    Endocrinology, 2010
    Co-Authors: Elise L V Malavasi, Brian R Walker, Val Kelly, Nikita Nath, Alessandra Gambineri, Rachel Dakin, Uberto Pagotto, Renato Pasquali, Karen E Chapman
    Abstract:

    Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11 beta-Hydroxysteroid Dehydrogenase type 1 (11 beta-HSD1) may be of pathophysiological importance in obesity and metabolic syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11 beta-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here, we have tested the functional consequences of two single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11 beta-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5'-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared with the common G allele, the A allele of rs13306421, a polymorphism located two nucleotides 5' to the translation initiation site, gave higher 11 beta-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of "leaky scanning." These data suggest that this polymorphism may have direct functional consequences on levels of 11 beta-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence because it was not detected in a population of 600 European Caucasian women.

  • dysregulation of glucocorticoid metabolism in murine obesity comparable effects of leptin resistance and deficiency
    Journal of Endocrinology, 2009
    Co-Authors: Brian R Walker, Dawn E W Livingstone, Sarah L Grassick, Gillian L Currie, Ruth Andrew
    Abstract:

    In obese humans, metabolism of glucocorticoids by 11 beta-Hydroxysteroid Dehydrogenase type 1 (11 beta-HSD1) and A-ring reduction (by 5 alpha- and 5 beta-reductases) is dysregulated in a tissue specific manner. These changes have been recapitulated in leptin resistant obese Zucker rats but were not observed in high-fat fed Wistar rats. Recent data from mouse models suggest that such discrepancies may reflect differences in leptin signalling. We therefore compared glucocorticoid metabolism in murine models of leptin deficiency and resistance. Male ob/ob and db/db mice and their respective littermate controls (n=10-12/group) were studied at the age of 12 weeks. Enzyme activities and mRNA expression were quantified in snap-frozen tissues. The patterns of altered pathways of steroid metabolism in obesity were similar in ob/ob and db/db mice. In liver, 5 beta-reductase activity and mRNA were increased and 11 beta-HSD1 decreased in obese mice, whereas 5 alpha-reductase 1 (5 alpha R1) mRNA was not altered. In visceral adipose depots, 5 beta-reductase was not expressed, 11 beta-HSD1 activity was increased and 5 alpha R1 mRNA was not altered in obesity. By contrast, in subcutaneous adipose tissue 11 beta-HSD1 and 5 alpha R1 mRNA were decreased. Systematic differences were not found between ob/ob and db/db murine models of obesity, suggesting that variations in leptin signalling through the short splice variant of the Ob receptor do not contribute to dysregulation of glucocorticoid metabolism.

  • 11 beta Hydroxysteroid Dehydrogenase type 1 11beta hsd1 inhibitors in type 2 diabetes mellitus and obesity
    Expert Opinion on Investigational Drugs, 2008
    Co-Authors: Katherine A Hughes, Scott P Webster, Brian R Walker
    Abstract:

    Background: Glucocorticoids such as cortisol are important regulators of fuel metabolism during starvation and stress. Chronic glucocorticoid excess induces obesity with multiple features of the metabolic syndrome. Objective: In this article, we review the importance of glucocorticoids in metabolic syndrome and the approaches that have been explored to reduce glucocorticoid action as the basis for novel therapy of Type 2 diabetes and obesity. Method: We focus on the enzyme 11-Beta-Hydroxysteroid Dehydrogenase type 1 (11β-HSD1), which amplifies glucocorticoid concentrations in key metabolic tissues including liver and adipose tissue. Results/conclusion: Several 11β-HSD1 inhibitors are in late preclinical or early clinical development and we review here the properties of the class leaders and their potential as the next generation of drugs with multiple benefits in metabolic syndrome.

  • subcutaneous adipose 11β Hydroxysteroid Dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in pima indians and caucasians
    The Journal of Clinical Endocrinology and Metabolism, 2003
    Co-Authors: Robert Lindsay, Deborah J Wake, Saraswathy Nair, Joy C Bunt, Dawn E W Livingstone, Paska A Permana, Antonio P Tataranni, Brian R Walker
    Abstract:

    Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-Hydroxysteroid Dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.

  • growth hormone replacement inhibits renal and hepatic 11β Hydroxysteroid Dehydrogenases in acth deficient patients
    Clinical Endocrinology, 1998
    Co-Authors: Brian R Walker, Ruth Andrew, Kenneth M Macleod, Paul L Padfield
    Abstract:

    OBJECTIVES The commonest side-effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11 beta-Hydroxysteroid Dehydrogenase (11 beta-HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism. DESIGN A randomized double-blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease. PATIENTS 6 men and 8 women received placebo and 8 men and 9 women received GH. MEASUREMENTS Cortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months. RESULTS Five patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326 +/- 191 to 777 +/- 229 micrograms/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88 +/- 0.10 to 2.57 +/- 0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo. CONCLUSIONS The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11 beta-HSD2 and the conversion of cortisone to cortisol by hepatic 11 beta-HSD1. It is unclear why this action of GH only affects patients with ACTH deficiency. The reduction in total cortisol metabolite excretion suggests that GH also affects bioavailability of hydrocortisone tablets. These observations suggest that glucocorticoid replacement therapy may need to be adjusted in hypopituitary patients who are commenced on GH replacement.

J I Mason - One of the best experts on this subject based on the ideXlab platform.

  • type 2 11 beta Hydroxysteroid Dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes its relationship to birth weight and putative role in fetal adrenal steroidogenesis
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Paul M. Stewart, F M Rogerson, J I Mason
    Abstract:

    Two isoforms of 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) have been described which catalyze the interconversion of cortisol (F) to cortisone (E). 11 beta HSD activity has previously been reported in placenta and fetal membranes, where its role may be to protect the developing fetus from glucocorticoid excess. Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported. We have characterized the isoforms of 11 beta HSD in human fetal membranes and dissected placental tissue at term and investigated the relationship between placental 11 beta HSD activity and fetal and placental weights. 11 beta HSD activity studies in the presence of 0.1 mumol/L F and NAD (indicative of type 2 isoform activity) revealed high levels of activity in trophoblast dissected free of vessels (561 +/- 87 pmol E/h.mg protein; n = 4) > undissected placenta > cotyledenous vessels dissected away from trophoblast > placental and reflected amnion. In contrast, in the presence of 2.5 mumol/L F and NADP (indicative of type 1 isoform activity), only decidua and chorion demonstrated significant levels of 11 beta HSD activity. Type 1 11 beta HSD activity in chorion was probably due to decidual contamination, in that it was absent in decidua-free fused chorion obtained from a twin pregnancy. In keeping with these data, type 1 11 beta HSD messenger ribonucleic acid (1.5 kilobases) was detected in decidua, but in no other tissue, and high levels of type 2 11 beta HSD messenger ribonucleic acid (1.9 kilobases) were found in undissected placenta and trophoblast. In 27 term placentas, 11 beta HSD activity varied from 194-448 pmol E/h.mg protein. There was a weak, but significant, positive correlation between term placental 11 beta HSD activity and fetal weight (r = 0.408; P = 0.034), but no correlation with placental weight. Thus, in man, the reported association of a small fetus and a large placenta predisposing to adult hypertension cannot be explained on the basis of defective 11 beta HSD activity. However, the placenta offers an immense reservoir for F clearance (1.73-7.95 mumol/min.placenta) and may be a principal factor driving fetal ACTH secretion and, hence, fetal adrenal steroidogenesis.

  • type 2 11 beta Hydroxysteroid Dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes its relationship to birth weight and putative role in fetal adrenal steroidogenesis
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Paul M. Stewart, F M Rogerson, J I Mason
    Abstract:

    Two isoforms of 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) have been described which catalyze the interconversion of cortisol (F) to cortisone (E). 11 beta HSD activity has previously been reported in placenta and fetal membranes, where its role may be to protect the developing fetus from glucocorticoid excess. Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported. We have characterized the isoforms of 11 beta HSD in human fetal membranes and dissected placental tissue at term and investigated the relationship between placental 11 beta HSD activity and fetal and placental weights. 11 beta HSD activity studies in the presence of 0.1 mumol/L F and NAD (indicative of type 2 isoform activity) revealed high levels of activity in trophoblast dissected free of vessels (561 +/- 87 pmol E/h.mg protein; n = 4) > undissected placenta > cotyledenous vessels dissected away from trophoblast > placental and...

  • human kidney 11 beta Hydroxysteroid Dehydrogenase is a high affinity nicotinamide adenine dinucleotide dependent enzyme and differs from the cloned type i isoform
    The Journal of Clinical Endocrinology and Metabolism, 1994
    Co-Authors: Paul M. Stewart, B A Murry, J I Mason
    Abstract:

    11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) catalyzes the conversion of cortisol to cortisone and plays an important role in the mammalian kidney in regulating cortisol access to the mineralocorticoid receptor. 11 beta HSD-deficient states, such as the syndrome of apparent mineralocorticoid excess (AME), and licorice ingestion result in hypertension in which cortisol acts as a mineralocorticoid. A gene and complementary DNA sequence encoding type I human 11 beta HSD have been described, but this gene is normal in patients with AME. Separate 11 beta HSD isoforms have been described in rat and rabbit kidney, but 11 beta HSD has not been characterized in human kidney. Kinetic analysis of 11 beta HSD activity in human fetal kidney microsomes revealed only a high affinity isoform (apparent Km, 60 nmol/L for cortisol, 13 nmol/L for corticosterone), the activity of which was exclusively nicotinamide adenine dinucleotide (NAD) dependent. No 11-oxo-reductase activity was seen in either renal homogenates or ...

Zygmunt S Krozowski - One of the best experts on this subject based on the ideXlab platform.

  • 11 beta Hydroxysteroid Dehydrogenase
    Vitamins and Hormones Series, 1999
    Co-Authors: Paul M. Stewart, Zygmunt S Krozowski
    Abstract:

    In mammalian tissues, at least two isozymes of 11 beta-Hydroxysteroid Dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent Dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid. By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression.

  • immunohistochemical localization of the 11 beta Hydroxysteroid Dehydrogenase type ii enzyme in human kidney and placenta
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Zygmunt S Krozowski, R E Smith, Julie A Maguire, Alicia N Steinoakley, John E Dowling, Robert K Andrews
    Abstract:

    It has been proposed that the inactivation of glucocorticoids by the enzyme 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) is an obligatory step in the kidney, permitting binding of aldosterone to the mineralocorticoid receptor, and in the placenta, protecting the fetus from high circulating levels of maternal glucocorticoids. Both low and high affinity isoforms of 11 beta HSD are known to exist, with evidence accumulating that the former species (11 beta HSD1) does not fulfill criteria that would allow it to perform these physiological functions. We have recently cloned a high affinity isoform of the enzyme (11 beta HSD2) from a human kidney library and have shown this species to possess all of the characteristics predicted from whole cell studies. In the present study we have raised a polyclonal antibody (HUH23) to a synthetic peptide deduced from the carboxy-terminus of the protein. The immunopurified antibody recognized a single band at 41,000 daltons on Western blots of mammalian cells transfected with an expression plasmid containing 11 beta HSD2, slightly smaller than the predicted 44,140 daltons protein. A single band of identical size was also seen in blots of human kidney and placenta, suggesting post-translational processing of the enzyme. Immunohistochemical studies on frozen sections of human kidney showed strong 11 beta HSD2 immunoreactivity in the cortical distal convoluted tubules and collecting ducts. Strong staining was also observed in medullary tubules, which had the appearance of collecting ducts and the thick ascending limb of Henle's loop. Staining of medium intensity was observed in vascular smooth muscle cells. Epithelial cells of glomeruli showed weak but detectable reactivity with HUH23. In the placenta, HUH23 antibody immunoreactivity was restricted to syncytial trophoblast cells in which strong staining was observed. These results suggest that the 11 beta HSD2 enzyme colocalizes with the mineralocorticoid receptor in the distal nephron where it allows aldosterone to occupy its physiological receptor. Furthermore, 11 beta HSD2 is also ideally situated in the placenta to protect the fetus from high circulating levels of maternal glucocorticoids.

  • cloning and tissue distribution of the human 11 beta Hydroxysteroid Dehydrogenase type 2 enzyme
    Molecular and Cellular Endocrinology, 1994
    Co-Authors: A L Albiston, Varuni R Obeyesekere, R E Smith, Zygmunt S Krozowski
    Abstract:

    : The enzyme 11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) is thought to protect the non-selective mineralocorticoid receptor from occupation by glucocorticoids, and to modulate access of glucocorticoids to glucocorticoid receptors resulting in protection of the fetus and gonads. A ubiquitous low affinity NADP+ dependent enzyme (11 beta HSD1) and a tissue specific, high affinity NAD+ dependent form (11 beta HSD2) of 11 beta HSD exist. We now report the isolation of a cDNA coding for human 11 beta HSD2. The new isoform is NAD+ dependent, exclusively Dehydrogenase in directionality, inhibited by glycyrrhetinic acid and metabolizes the synthetic glucocorticoid dexamethasone; it displays Km values for corticosterone and cortisol of 5.1 nM and 47 nM, respectively. Sequence alignment shows that 11 beta HSD2 shares 35% identity with 17 beta HSD2, but is only 14% identical with 11 beta HSD1. The 11 beta HSD2 gene is highly expressed in kidney, colon, pancreas and placenta and the message is also present in the ovary, prostate and testis. These data suggest that 11 beta HSD2 plays an important role in modulating mineralocorticoid and glucocorticoid receptor occupancy by glucocorticoids.

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

  • maternal prenatal licorice consumption alters hypothalamic pituitary adrenocortical axis function in children
    Psychoneuroendocrinology, 2010
    Co-Authors: Katri Raikkonen, Jonathan R Seckl, Anukatriina Pesonen, Kati Heinonen, Jari Lahti, Riikka Pyhala, Kimmo Feldt, Alexander Jones, David I W Phillips, Annaliisa Jarvenpaa
    Abstract:

    Overexposure to glucocorticoids has been proposed as a mechanism by which prenatal adversity 'programs' the function of the hypothalamic pituitary adrenocortical axis (HPAA), thereby increasing the risk of adult diseases. Glycyrrhizin, a natural constituent of licorice, potently inhibits 11 beta-Hydroxysteroid Dehydrogenase type 2, the feto-placental barrier to the higher maternal cortisol levels. We studied if maternal consumption of glycyrrhizin in licorice associates with HPAA function in children. Diurnal salivary cortisol and salivary cortisol during the Trier Social Stress Test for Children (TSST-C) were measured in children (n = 321, mean age = 8.1, SD = 0.3 years) whose mothers consumed varying levels of glycyrrhizin in licorice during pregnancy; exposure-level groups were labeled high (>= 500 mg/week), moderate (250-499 mg/week) and zero low (0-249 mg/week). In comparison to the zero low exposure group, children in the high exposure group had 19.2% higher salivary cortisol awakening peak, 33.1% higher salivary cortisol awakening slope, 15.4% higher salivary cortisol awakening area under the curve (AUC), 30.8% higher baseline TSST-C salivary cortisol levels, and their salivary cortisol levels remained high throughout the TSST-C protocol (P-values <0.05). These effects appeared dose-related. Our findings lend support to prenatal 'programming' of HPAA function by overexposure to glucocorticoids. (C) 2010 Elsevier Ltd. All rights reserved.

  • maternal licorice consumption and detrimental cognitive and psychiatric outcomes in children
    American Journal of Epidemiology, 2009
    Co-Authors: Katri Raikkonen, Jonathan R Seckl, Anukatriina Pesonen, Kati Heinonen, Jari Lahti, Niina Komsi, Johan G Eriksson, Annaliisa Jarvenpaa, Timo E Strandberg
    Abstract:

    Overexposure to glucocorticoids may link prenatal adversity with detrimental outcomes in later life. Glycyrrhiza, a natural constituent of licorice, inhibits placental 11-Beta-Hydroxysteroid Dehydrogenase type 2, the feto-placental ‘‘barrier’’ to higher maternal levels of cortisol. The authors studied whether prenatal exposure to glycyrrhiza in licorice exerts detrimental effects on cognitive performance (subtests of the Wechsler Intelligence Scale for Children III as well as the Children’s Developmental Neuropsychological Assessment and the Beery Developmental Test of Visual-Motor Integration) and psychiatric symptoms (Child Behavior Checklist) in 321 Finnish children 8.1 years of age born in 1998 as healthy singletons at 35–42 weeks of gestation. In comparison to the group with zero–low glycyrrhiza exposure (0–249 mg/week), those with high exposure (� 500 mg/week) had significant decrements in verbal and visuospatial abilities and in narrative memory (range of mean differences in standard deviation units, � 0.31 to � 0.41; P < 0.05) and significant increases in externalizing symptoms and in attention, rule-breaking, and aggression problems (range of odds ratios, 2.15 to 3.43; P < 0.05). The effects on cognitive performance appeared dose related. Data are compatible with adverse fetal ‘‘programming’’ by overexposure to glucocorticoids and caution against excessive intake of licorice-containing foodstuffs during pregnancy. child; cognition; glucocorticoids; glycyrrhiza; glycyrrhizic acid; mental disorders; 11-Beta-Hydroxysteroid Dehydrogenase type 2

  • placental 11β Hydroxysteroid Dehydrogenase a key regulator of fetal glucocorticoid exposure
    Clinical Endocrinology, 1997
    Co-Authors: Rafn Benediktsson, Christopher R. W. Edwards, A A Calder, Jonathan R Seckl
    Abstract:

    Objective Placental 11 beta-Hydroxysteroid Dehydrogenase (11 beta-HSD), which converts active cortisol to inactive cortisone, has been proposed to be the mechanism guarding the fetus from the growth retarding effects of maternal glucocorticoids; however, other placental enzymes have also been implicated. Placental 11 beta-HSD is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role. We have therefore examined placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas. Design Placentas were obtained from randomly selected normal term deliveries. The maternal circuit was perfused with physiological concentration of cortisol, the fetal effluent collected and steroid metabolites separated and quantified using silica columns (Sep-pak Plus) and HPLC. Results Most of the maternally administered cortisol was metabolized to cortisone, and no conversion of cortisone to cortisol was detected. Cortisone was the only product of cortisol metabolism. Inhibition of 11 beta-HSD with glycyrrhetinic acid allowed cortisol to gain direct access to the fetal circulation. Conclusion We conclude that human placental 11 beta-HSD plays a crucial role in controlling glucocorticoid access to the fetus. Other enzymes are not significant contributors at physiologically relevant cortisol concentrations.

  • glucocorticoids feto placental 11 beta Hydroxysteroid Dehydrogenase type 2 and the early life origins of adult disease
    Steroids, 1997
    Co-Authors: Jonathan R Seckl
    Abstract:

    Increasing human epidemiological data suggest that events that subtly retard intrauterine growth may determine common disorders, such as hypertension and non-insulin-dependent diabetes, in adult life. The underlying mechanisms are unknown. However, excessive fetal exposure to glucocorticoids retards growth and "programs" adult hypertension in rats. 11 beta-Hydroxysteroid Dehydrogenase type 2 (11 beta-HSD2) catalyzes the rapid inactivation of cortisol and corticosterone to inert 11 keto-products. Normally, 11 beta-HSD2 in the placenta and some fetal tissues is thought to protect the fetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD2, and enzyme activity correlates with birth weight. Moreover, inhibition of feto-placental 11 beta-HSD2 in the rat reduces birth weight and produces hypertensive and hyperglycaemic adult offspring, many months after prenatal treatment; effects are dependent upon intact maternal adrenals, suggesting a direct action on the fetus or placenta. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD2 activity. These data suggest that feto-placental 11 beta-HSD2, by regulating fetal exposure to maternal glucocorticoids, crucially determines fetal growth and the programming of later disorders. Deficiency of the barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and feto-placental programming of later disease. These data may, at least in part, explain the human observations linking early life events to the risk of subsequent disease.

  • 11 beta Hydroxysteroid Dehydrogenase is an exclusive 11 beta reductase in primary cultures of rat hepatocytes effect of physicochemical and hormonal manipulations
    Endocrinology, 1995
    Co-Authors: Pauline M Jamieson, Christopher R. W. Edwards, Karen E Chapman, Jonathan R Seckl
    Abstract:

    11 beta-Hydroxysteroid Dehydrogenase (11 beta HSD) catalyzes the conversion of corticosterone to inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors. This type 1 isoform (11 beta HSD-1) is a bidirectional NADPH(H)-dependent enzyme in vitro and is highly expressed in liver, where it is regulated by glucocorticoids, thyroid hormones, estrogen, and GH in vivo. In humans in vivo, enzyme inhibition alters glucose homeostasis, an effect thought to be mediated in the liver. However, detailed investigation of the biology of 11 beta HSD-1 in liver, its function, regulation, and indeed even reaction direction, has been hampered by the lack of clonal hepatic cell lines that express 11 beta HSR-1. Studies of nonhepatic cell lines have suggested that 11 beta HSD-1 is directly regulated by hormones, and transfection of nonhepatic cell lines has sown that reaction direction varies between cell types, possibly reflecting intracellular cosubstrate (NADP+/NADPH) ratios or PH. To...