Role of 11beta-hydroxysteroid Dehydrogenase Inhibitors in Metabolic Syndrome and its Expansion in other Therapeutic Options

B. Rajkapoor; Ali Dau Masoud; Abdussalam Sughir; A. Vijayakumar

Authors

B. Rajkapoor Department of Pharmacology, Faculty of Medicine, Sebha University, Sebha, Libya
Ali Dau Masoud Department of Pharmacology, Faculty of Medicine, Sebha University, Sebha, Libya
Abdussalam Sughir Faculty of Pharmacy, University of Almergib, Alkhoms, Libya
A. Vijayakumar Drug and Poison Information Center, Department of Pharmacy Practice, KMCH College of Pharmacy, Coimbatore, India

Keywords:

11 Beta hydroxysteroid dehydrogenase inhibitors, Metabolic syndrome, Glucocorticoids, Obesity, Type 2 diabetes

Abstract

The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to promote the development of diabetes and cardiovascular disease. These risk factors include abdominal obesity, insulin resistance, hypertension and dyslipidemia. 11beta-Hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the interconversion of glucocorticoids through the activity of two isozymes: type 1 (11beta-HSD1) and type 2 (11beta-HSD2). 11beta-HSD1 converts inactive glucocorticoid to the active form, whereas 11beta-HSD2 converts active glucocorticoid to the inactive form. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. . This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, osteoporosis due to the role of glucocorticoids and cellular activation by 11 beta HSD1 in these pathologies.

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References

Adcock I M,Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid. Redox. Signal 2005;7:144-52.

Adcock I M, Ito K, Barnes P J. Glucocorticoids: effects on gene transcription. Proc.Am. Thorac.Soc 2004; 1: 247-54

Barnes P.J,Adcock I. Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol. Sci.1993;14: 436-41

Nonogaki K,Iguchi A. Role of central neural mechanisms in the regulation of hepatic glucose metabolism. Life Sci.1997; 60: 797-807.

Agarwal A K, Monder C, Eckstein B, White P C.Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase. J. Biol. Chem. 1989; 264: 18939–43

Stewart P M.Tissue-specific Cushing’s syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. Eur. J. Endocrinol. 2003; 149: 163–68.

Albiston A L, V R Obeyesekere, R E Smith, Z S Krozowski.Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol. Cell. Endocrinol. 1994;105:R11–17.

Walker B R, J.R Seckl.11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease.Expert Opin. Ther. Targets. 2003; 7:771–83

Thieringer R, Hermanowski-Vosatka A. Inhibition of 11beta-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?. Exp. Rev. Cardiovasc.Ther.2005; 3: 911-24.

Bahr V, Pfeiffer A.F, Diederich S. The metabolic syndrome X and peripheral cortisol synthesis. Exp. Clin. Endocrinol. Diabetes. 2002;110: 313-18

Masuzaki H, J.S. Flier.Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)–a promising drug target for the treatment of metabolic syndrome. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2003;3:255–62.

Thieringer R, Hermanowski-Vosatka, A. Inhibition of 11beta-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?. Exp. Rev. Cardiovasc. Ther.2005; 3 :911-924.

Tomlinson J.W, Walker E.A, Bujalska I.J, Draper N, Lavery G.G, Cooper M.S, Hewison M, Stewart P.M. 11ß-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response.Endocr. Rev.2005; 25: 831-66

Ulick S, Levine LS, Gunczler P, et al. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 1979; 49:757-64.

Walker B R, Connacher A A, Lindsay R M, Webb D J, Edwards C R. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J. Clin. Endocrinol. Metab.1995; 80: 3155–59

Seckl JR, Walker BR. 11beta Hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology.2001;142: 1371–76

Jamieson PM, Walker BR, Chapman KE, Andrew R, Rossiter S, Seckl JR. 11beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver. J Endocrinol.2000;165: 685-

Low S C, Chapman KE, Edwards C R, Seckl J R. 'Liver-type' 11 beta-hydroxysteroid dehydrogenase cDNA encodes reductase but not dehydrogenase activity in intact mammalian COS-7 cells.J. Mol. Endocrinol.1994;13:167-74.

Jamieson P M, Chapman K E, Edwards C R, Seckl J R. 11ß-Hydroxysteroid dehydrogenase is an exclusive 11ß-reductase in primary cultured rat hepatocytes: effect of physicchemical and hormonal manipulations. Endocrinology.1995;136: 4754-61

Voice M W, Seckl J R, Edwards C R, Chapman K E. 11ß-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism Biochem. J.1996; 317:621-25

Kotelevtsev Y, Holmes M C, Burchell A, Houston P M, Schmoll D , Jamieson P,et al 11ß-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. .Proc. Natl. Acad. Sci. USA.1997; 94:14924-129.

Hewitt KN, EA Walker, P.M. Stewart. Hexose-6-phosphate dehydrogenase and redox control of 11 beta hydroxysteroid dehydrogenase type 1 activity. Endocrinology.2005;146: 2539–43

Banhegyi G, A Benedetti, R Fulceri, S. Senesi.Cooperativity between 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the lumen of the endoplasmic reticulum. J. Biol. Chem. 2004;279: 27017–21

Atanasov AG, LG Nashev, RAS Schweizer, et al. Hexose-6-phosphate dehydrogenase determines the reaction direction of 11betahydroxysteroid Dehydrogenase type 1 as an oxoreductase. FEBS Lett. 2004;571: 129–33.

Thieringer R, Le Grand CB, Carbin L, Cai TQ, Wong B, Wright SD, Hermanowski-Vosatka A.11beta-Hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J. Immunol. 2001;167: 30–35

Hammani MM, PK Siiteri.Regulation of 11 beta hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J. Clin. Endocrinol. Metab.1991;73: 326–34

Moore JS, JP Monson, G Kaltsas, et al.Modulation of 11 beta hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 1999;84: 4172– 77

Trainer PJ, Drake WM, Perry LA, Taylor NF, Besser GM, Monson JP. Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly. J. Clin. Endocrinol. Metab.2001; 86: 2989–92

Berger J, Tanen M, Elbrecht A, Hermanowski-Vosatka A, Moller D E, Wright S D. Peroxisome proliferator activated receptor- ligands inhibit adipocyte 11beta-hydroxysteroid dehydrogenase type 1 expression and activity. J. Biol. Chem.2001; 276: 12629–35

Hermanowski-Vosatka A, D Gerhold, SS.Mundt, et al.. PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver.Biochem.Biophy.Res. Commun. 2000; 279: 330–36.

Stulnig, T M, U Oppermann K R, Steffensen, et al. PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver. Biochem. Biophy. Res. Commun. 2002; 279: 330–36.

Morton NM, L Ramage, JR Seckyl.Downregulation of adipose 11 beta hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism counteracting metabolic disease. Endocrinology. 2004; 145: 2707–12.

Bujalska IJ, Walker E.A, Hewison M, Stewart PM. A switch in dehydrogenase to reductase activity of 11-ß hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells. J.Clin.Endocrinol. Metab.2002;87:1205-10.

Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. Endocr. Res.2002;28:449-61.

Tomlinson JW, Sinha B, Bujalska I, Hewison M, Stewart PM. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J. Clin. Endocrinol. Metab. 2002; 87:5630-35.

Tomlinson JW, Moore J, Cooper MS, Bujalska I., Shahmanesh M, Burt C, Strain A, Hewison M, Stewart PM. Regulation of expression of 11-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines Endocrinology. 2001; 142:1982-89.

Franks PW, Knowler WC, Nair S, Koska J, Lee YH, Lindsay RS,et al.Interaction between an 11betaHSD1 gene variant and birth era modifies the risk of hypertension in Pima Indians. Hypertension.2004; 44: 681–88.

Caramelli E, P Strippoli, T DI Giacomi, et al.Lack of mutations of type 1 11[beta]-hydroxysteroid dehydrogenase gene in patients with abdominal obesity. Endocr. Res. 2001;27: 47–61.

Draper N, SM Echwald, GG Lavery, et al. Association studies between microsatellite markers within the gene encoding human 11betahydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism. J. Clin. Endocrinol. Metab.2002; 87: 4984–90.

Gelernter-Yaniv L, Feng N, Sebring NG, Hochberg Z, Yanovski JA.Associations between polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition. Int. J. Obes. Relat. Metab. Disord 2003; 27: 983–86.

Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, Guhathakurta D, et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat. Genet 2005; 37: 710–17.

Otieno CJ, Bastiaansen J, Ramos AM, Rothschild MF. Mapping and association studies of diabetes related genes in the pig. Anim. Genet 2005; 36:36–42.

Reus VI, OM Wolkowitz. Antiglucocorticoid drugs in the treatment of depression. Expert Opin. Investig. Drugs.2001;10:1789– 96.

Reus VI, Wolkowitz OM. Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol. Psychol.1999; 45: 1070– 74.

Gaillard RC, Poffet D, Riondel AM, Saurat JH. RU486 inhibits peripheral effects of glucocorticoids in humans. J. Clin. Endocrinol. Metab 1985; 61:1009–11.

Jacobson P B, von Geldern T W, Ohman L, Osterland M, Wang J, Zinker B, et al. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. J. Pharmacol. Exp. Ther 2005; 314: 191–200.

Stewart P M, A M Wallace, S M Atherden, et al. Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta hydroxysteroid dehydrogenase activity in man. Clin. Sci 1990;78: 49– 54.

Andrew R, K Smith, GC Jones, B R Walker.Distinguishing the activities of 11 beta hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol. J. Clin. Endocrinol. Metab 2002; 87: 277–285.

Andrews R C, O Rooyackers, B R Walker. Effects of the 11 beta hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J. Clin. Endocrinol. Metab 2003; 88: 285–91.

Livingstone DE, Walker BR.Is 11 beta hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. J. Pharmacol. Exp. Ther 2003; 305: 167–72.

Li RS, Nakagawa Y, Nakanishi T, Fujisawa Y, Ohzeki T. Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats. Metabolism 2004; 53: 600–606.

Barf T, Vallgarda J, Emond R, Häggström C, Kurz G, Nygren A, et al. Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11 beta hydroxysteroid dehydrogenase type 1. J. Med. Chem 2002; 45: 3813–15.

Xiang J, Ipek M, Suri V, Massefski W, Pan N, Ge Y, et al. Synthesis and biological evaluation of sulfonamidooxazoles and keto sulfones:selective inhibitors of 11_-hydroxysteroid dehydrogenase type 1. Bioorg. Med. Chem. Lett 2005; 15: 2865–69.

Hult M, H Jornvall, U C T ppermann. Selective inhibition of human type 1 11bhydroxysteroid dehydrogenase by synthetic steroids and xenobiotics.Fed. Eur. Biochem. Stud.1998; 441: 25–28.

Alberts P, L Engblom, N Edling, et al. Selective inhibition of 11betahydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia.2002; 45: 1528–32.

Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, et al. Selective inhibition of 11 beta hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycaemic mice strains. Endocrinology.2003; 144: 4755–62.

Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, et al. 11 beta HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med 2005; 202: 517–27.

Walker BR, Yau JL, Brett LP, Seckl JR, Monder C, Williams BC, et al. 11beta-Hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinology 1991; 129: 3305–12.

Hadoke PWF, C Christy, YV Kotelevtsev, B. C. Williams, C. J. Kenyon, J. R. Seckl, et al .Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11beta- hydroxysteroid dehydrogenase. Circulation 2001;104: 2832–37.

Small G R, Hadoke P W, Sharif I, Dover A R, Armour D, Kenyon C J, et al. Preventing regeneration of glucocorticoids by 11 beta hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc. Natl. Acad. Sci. USA .2005;102: 12165–70

Wang MS, Shi H, Wang KS, Reidenberg MM. Inhibition of 11beta-hydroxysteroid dehydrogenase in guinea pig kidney by three bioflavonoids and their interactions with gossypol. Acta Pharmacol. Sin.2002; 23: 92-96.

Thieringer R, Le Grand CB, Carbin L, Cai TQ, Wong B, Wright SD, et al.11beta-Hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation tomacrophages. J. Immunol. 2001;167: 30–35.

Walker BR, Yau JL, Brett LP, Seckl JR, Monder C, Williams BC, et al.11 beta Hydroxysteroid dehydrogenasein vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinology .1991;129: 3305–12.

Hadoke PWF, C Christy, Y V Kotelevtsev, et al. Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11 beta hydroxysteroid dehydrogenase. Circulation.2001; 104: 2832–37.

Small GR, Hadoke PW, Sharif I, Dover AR, Armour D, Kenyon CJ, et al.Preventing regeneration of glucocorticoids by 11 beta hydroxysteroid dehydrogenase type 1 enhances angiogenesis.Proc. Natl. Acad. Sci. USA.2005; 102: 12165–70.

Harris HJ, YV Kotelevtsev, JJ Mullins, et al.11 beta Hydroxysteroid dehydrogenase type 1 null mice have altered hypothalamicpituitary-adrenalaxis activity: a novel control of glucocorticoid feedback. Endocrinology. 2001; 142:114–20.

Yau JL, Noble J, Kenyon CJ, Hibberd C, Kotelevtsev Y, Mullins JJ, et al.Lack of tissue glucocorticoid reactivation in 11 beta hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc. Natl. Acad. Sci. USA .2001;98:4716–21.

Sandeep TC, Yau JL, MacLullich AM, Noble J, Deary IJ, Walker BR, et al.11 beta hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc. Natl. Acad. Sci. USA.2004;101: 6734–39.

Stulnig TM, Oppermann U, Steffensen KR, Schuster GU, Gustafsson JA. Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity. Diabetes 2002; 51:2426-33.

Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ,et al Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J. Biol.Chem 2003; 278:131-36.

Laffitte BA , Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, et al. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue.Proc. Natl. Acad.Sci. USA 2003; 100: 5419-24.

Kurukulasuriya R, Link JT, Madar DJ, Pei Z, Richards SJ, Rohde J , Souers AJ, Szczepankiewicz BG. Potential drug targets and progress towards pharmacological inhibition of hepatic glucose production. Curr. Med.Chem 2003; 10:123-53.

Link JT. Pharmacological regulation of hepatic glucose production. Curr. Opin. Investig. Drugs 2003; 4:421-29.

Jacobson PB, von Geldern TW, Ohman L, Osterland M, Wang J, Zinker B, et al. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes..J. Pharmacol. Exp. Ther 2005; 314:191-200.

Valsamakis G, Anwar A, Tomlinson JW, Shackleton CH, McTernan PG, Chetty R, et al. 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab 2004; 89: 4755-61.

Lakshmi V, Sakai RR, McEwen BS, Monder C. Regional Distribution of 1 β-Hydroxysteroid Dehydrogenase in Rat Brain Endocrinology 1991; 128: 1741-48.

Basu R, Singh R J, Basu A, Chittilapilly E G, Johnson C M, Toffolo G, et al. Splanchnic cortisol production occurs in humans – evidence for conversion of cortisone to cortisol via the 11 beta hydroxysteroid dehydrogenase type 1 pathway. Diabetes 2004;53: 2051–59.

Liu Y, Nakagawa Y, Wang Y, Li R, Li X,et al.. Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes 2003; 52: 1409–16.

Tomlinson JW, Moore JS, Clark PM, Holder G, Shakespeare L, Stewart PM. Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J. Clin. Endocrinol. Metab 2004; 89: 2711–16.

Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Heintze U, Janke J, et al. Regulation of 11 beta hydroxysteroid dehydrogenase genes in human adipose tissue: influence of central obesity and weight loss. Obes. Res.2004; 12: 9–17.

De Kloetm E.R. Stress in brain.Eur. J. Pharmacol 2000; 405: 187-198.

De Kloet E.R, Hormones and the stressed brain. Ann. N.Y. Acad. Sci.2004; 1018: 1-15.

De Kloet, ER Vreugdenhil, E Oitzl, M.S, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev 1998; 19: 269-301.

Moisan M P, Seckl J R. Edwards CR. 11β-Hydroxysteroid Dehydrogenase Bioactivity And Messenger RNA Expression In Rat Forebrain: Localization In Hypothalamus, Hippocampus, And Cortex. Endocrinology 1990; 127: 1450-1455.

Low S C, Moisan M P, Noble J M, Edwards C R, Seckl J R. Glucocorticoids and chronic stress upregulate 11ß-hydroxysteroid dehydrogenase activity and gene expression in the hippocampus. J. Neuroendocrinol.1994; 6: 285-90.

Rajan V, Edwards CR, Seckl JR. 11 beta-Hydroxysteroid dehydrogenase in cultured hippocampal cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity. J. Neurosci 1996;16: 65-70.

Yau JL, Noble J, Kenyon CJ, Hibberd C, Kotelevtsev Y, Mullins JJ, Seckl JR. Lack of tissue glucocorticoid reactivation in 11beta - hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc. Natl. Acad. Sick. USA 2001;98: 4716-21.

Sandeep T C, Yau J L, MacLullich A M, Noble J, Deary I J, Walker B R, Seckl J R. 11 β- hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics.Proc. Natl. Acad. Sci. USA 2004; 101: 6734-39.

De Quervain D J, Poirier R, Wollmer M A, Grimaldi L M, Tsolaki M, Streffer J R, et al. Glucocorticoid-related genetic susceptibility for Alzheimer's disease. Hum. Mol. Genet 2004; 13: 47-52.

Rauz S, Walker EA, Shackleton CH, Hewison M, Murray PI, Stewart PM. Invest. Expression and putative role of 11â-hydroxysteroid dehydrogenase isozymes within the human eye. Ophthalmol.Vis. Sci 2001; 42:2037-42.

Rauz S, Cheung C M, Wood P J, Coca-Prados M, Walker E A, Murray P I, et al . Inhibition of 11beta-hydroxysteroid dehydrogenase type. 1 lowers intraocular pressure in patients with ocular hypertension.QJM 2003; 96:481-90.

Hench PS. Nobel Lecture, http://nobelprize.org/medicine/? wp_ml=0.

Barnes P J.Adcock I M. Steroid resistance in asthma QJM 1995; 88: 455-68.

Wilckens T. Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunctionTrends Pharmacol. Sci 1995; 16:193-97.

Wilckens T, De Rijk R. Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol. Today 1997; 18: 418-24.

Munck A, Naray-Fejes-Toth A. The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol. Cell Endocrinol.1992;90: C1-4.

Zhou Z,Shackleton C H, Pahwa S, White P C, Speiser PW. Prominent sex steroid metabolism in human lymphocytes. Mol. Cell Endocrinol.1998; 138: 61-69.

Hennebold J D, Ryu S Y, Mu H H,Galbraith A, Daynes R A. 11β-hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lymphoid organs. Am. J. Physiol 1996; 270: R1296-1306.

Freeman L, Hewison M, Hughes SV, Evans KN, Hardie D, Mean TK. Expression of 11beta-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells.Blood 2005; 106: 2042-49.

Teelucksingh S, Mackie A D, Burt D, McIntyre M A, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990; 335:1060-63.

Hennebold J D, Mu H H, Poynter M E, Chen X P, Daynes RA. Active catabolism of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase in vivo is a necessary requirement for natural resistance to infection with Listeria monocytogenes.Int. Immunol 1997; 9: 105-115.

Manelli F, Giustina A. Glucocorticoid-induced osteoporosis. Metab 2000;11: 79-85.

Doga M, Bonadonna S, Burattin A, Carpinteri R, Manelli F, Giustina A. Bisphosphonates in the Treatment of Glucocorticoid-Induced Osteoporosis. Front. Horm. Res .2002; 30:150-164.

Cooper M S, Rabbitt E H, Goddard P E, Bartlett W A, Hewison M, Stewart P M. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J. Bone Miner. Res 2002; 17: 979-86.

Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM. Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone.Bone.2000; 27:375-81.

Cooper MS, Blumsohn A, Goddard PE, Bartlett WA, Shackleton CH, Eastell R, et al. 11β hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J. Clin. Endocrinol. Metab 2003; 88:3874-77.

Justesen J, Mosekilde L, Holmes M, Stenderup K, Gasser J, Mullins J J, et al. Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation. Endocrinology 2004.145:1916-25.