Horm Metab Res 2011; 43(1): 66-71
DOI: 10.1055/s-0030-1267170
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

In Vivo Activity of 11β-Hydroxysteroid Dehydrogenase Type 1 in Man: Effects of Prednisolone and Chenodesoxycholic Acid

S. Diederich1 , 2 , M. Quinkler3 , K. Mai1 , M. Schöneshöfer4 , V. Baehr1 , A. Pfeiffer1 , W. Oelkers1 , 2 , E. Eigendorff1
  • 1Department of Endocrinology, Diabetes and Nutrition, Charité Campus Benjamin Franklin, Berlin, Germany
  • 2Endokrinologikum Berlin, Centre for Endocrine and Metabolism Diseases, Berlin, Germany
  • 3Clinical Endocrinology, Centre for Internal Medicine, Gastroenterology, Hepatology and Endocrinology, Charité Campus Mitte, Berlin, Germany
  • 4Department of Clinical Chemistry, Krankenhaus Berlin-Spandau, Berlin, Germany
Further Information

Publication History

received 25.06.2010

accepted 31.08.2010

Publication Date:
05 October 2010 (online)

Abstract

The 11β-hydroxysteroid dehydrogenases (11β-HSDs) play a pivotal role in glucocorticoid (GC) action. 11β-HSD1 is a predominant reductase, activating GCs from inert metabolites, whereas 11β-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic effects of GCs, a selective inhibition of 11β-HSD1 represents a potential target for therapy of impaired glucose tolerance, insulin insensitivity and central obesity. In vitro, 11β-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone on hepatic 11β-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone (E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers within a randomised cross-over trial before and after oral administration of 12.5 mg E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11β-HSD1 activity, hepatic reduction of 25 mg E acetate before and after treatment with prednisolone (30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined using a fully automated liquid chromatographic system. CDCA had no effect on the activity of 11β-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11β-HSD1, which could not be extinguished by a parallel increase of IGF-1 under prednisolone. CDCA does not affect in vivo activity of 11β-HSD1 when given in therapeutic dosages. During GC treatment, increased hepatic activation of E to F may aggravate metabolic side effects of GCs such as seen in the metabolic syndrome.

References

  • 1 Agarwal MK, Mirshahi M. General overview of mineralocorticoid hormone action.  Pharmacol Ther. 1999;  84 273-326
  • 2 Ballard PL, Carter JP, Graham BS, Baxter JD. A radioreceptor assay for evaluation of the plasma glucocorticoid activity of natural and synthetic steroids in man.  J Clin Endocrinol Metab. 1975;  41 290-304
  • 3 Stewart PM, Krozowski ZS. 11 beta-Hydroxysteroid dehydrogenase.  Vitam Horm. 1999;  57 249-324
  • 4 Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase – tissue specific protector of the mineralocorticoid receptor.  Lancet. 1988;  2 (8618) 986-989
  • 5 Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM. Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues.  J Clin Endocrinol Metab. 1998;  83 1325-1335
  • 6 Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1 - a tissue-specific amplifier of glucocorticoid action.  Endocrinology. 2001;  142 1371-1376
  • 7 Bahr V, Pfeiffer AF, Diederich S. The metabolic syndrome X and peripheral cortisol synthesis.  Exp Clin Endocrinol Diabetes. 2002;  110 313-318
  • 8 Staab CA, Maser E. 11 β-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation.  J Steroid Biochem Mol Biol. 2010;  119 56-72
  • 9 Morton NM. Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease.  Mol Cell Endocrinol. 2010;  316 154-164
  • 10 Cooper MS, Stewart PM. 11β-Hydroxysteroiddehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome and inflammation.  J Clin Endocrinol Metab. 2009;  94 4645-4654
  • 11 Veilleux A, Rheaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11β-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution and metabolic alterations in women.  J Clin Endocrinol Metab. 2009;  94 3550-3557
  • 12 Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A Transgenic Model of Visceral Obesity and the Metabolic Syndrome.  Science. 2001;  294 2166-2170
  • 13 Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ. 11beta-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 14924-14929
  • 14 Bujalska IJ, Kumar S, Hewison M, Stewart PM. Differentiation of adipose stromal cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase.  Endocrinology. 1999;  140 3188-3196
  • 15 Hammami MM, Siiteri PK. Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action.  J Clin Endocrinol Metab. 1991;  73 326-334
  • 16 Voice MW, Seckl JR, Edwards CR, Chapman KE. 11 beta-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;  317 621-625
  • 17 Quinkler M, Troeger H, Eigendorff E, Maser-Gluth C, Stiglic A, Oelkers W, Bähr V, Diederich S. Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig.  J Endocrinol. 2003;  176 185-192
  • 18 Sai S, Esteves CL, Kelly V, Michailidou Z, Anderson K, Coll AP, Nakagawa Y, Ohzeki T, Seckl JR, Chapman KE. Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase is indirect and requires CCAAT/enhancer-binding protein-β.  Mol Endocrinol. 2008;  22 2049-2060
  • 19 Quinkler M, Oelkers W, Diederich S. Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases in target tissues.  Eur J Endocrinol. 2001;  144 87-97
  • 20 Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CR. 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 3155-3159
  • 21 Alberts P, Engblom L, Edling N, Forsgren M, Klingstrom G, Larsson C, Rönquist-Nii Y, Ohman B, Abrahmsen L. Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice.  Diabetologia. 2002;  45 1528-1532
  • 22 Barf T, Vallgarda J, Emond R, Haggstrom C, Kurz G, Nygren A, Larwood V, Mosialou E, Axellson K, Olsson R, Engblom L, Edling N, Rönquist-Nii Y, Ohman B, Alberts P, Abrahmsen L. Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1.  J Med Chem. 2002;  45 3813-3815
  • 23 Su X, Vicker N, Truselle M, Halem H, Culler MD, Potter BV. Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1.  Mol Cell Endocrinol. 2009;  301 169-173
  • 24 Hadoke PWF, Iqbal J, Walker BR. Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease.  Br J Pharmacol. 2009;  156 689-712
  • 25 Maeda Y, Naganuma S, Niina I, Shinohara A, Koshimoto C, Kondo K, Chijiiwa K. Effects of bile acids on rat hepatic microsomal type I 11β-hydroxysteroid dehydrogenase.  Steroids. 2010;  75 164-168
  • 26 Diederich S, Grossmann C, Hanke B, Quinkler M, Herrmann M, Bahr V, Oelkers W. In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I.  Eur J Endocrinol. 2000;  142 200-207
  • 27 Ponz de Leon M, Loria P, Carulli N, Murphy G, Dowling R. Intestinal solubilization, absorption, pharmacokinetics and bioavailability of chenodesoxycholic acid.  Eur J Clin Invest. 1980;  10 261-271
  • 28 Stewart PM, Wallace AM, Atherden SM, Shearing CH, Edwards CR. Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man.  Clin Sci. 1990;  78 49-54
  • 29 Mai K, Kullmann V, Bobbert T, Maser-Gluth C, Möhlig M, Bähr V, Pfeiffer AFH, Spranger J, Diederich S. In vivo activity of 11beta-hydroxysteroid- dehydrogenase type 1 and free fatty acids induced insulin resistance.  Clin Endocrinol. 2005;  63 442-449
  • 30 Mai K, Andres J, Bobbert T, Maser-Gluth C, Möhlig M, Bähr V, Pfeiffer AFH, Spranger J, Diederich S. Rosiglitazone decreases 11beta-hydroxysteroid- dehydrogenase type 1 in subcutaneous adipose tissue.  Clin Endocrinol. 2007;  67 419-425
  • 31 Otto B, Tschoep M, Heldwein W, Pfeiffer AFH, Diederich S. Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.  Eur J Endocrinol. 2004;  151 113-117
  • 32 Diederich S, Hanke B, Burkhardt P, Müller M, Schöneshöfer M, Bähr V, Oelkers W. Metabolism of synthetic corticosteroids by 11β-hydroxysteroid-dehydrogenases in man.  Steroids. 1998;  63 271-277
  • 33 Diederich S, Eigendorff E, Burkhard P, Quinkler M, Bumke-Vogt C, Rochel M, Seidelmann D, Esperling P, Oelkers W, Bähr V. 11β-hydroxysteroid dehydrogenase type 1 and 2: An important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids.  J Clin Endocrinol Metab. 2002;  87 5695-5701
  • 34 Schoneshofer M, Fenner A. A convenient and efficient method for the extraction and fractionation of steroid hormones from serum or urine.  J Clin Chem Clin Biochem. 1981;  19 71-74
  • 35 Ricketts ML, Shoesmith KJ, Hewison M, Strain A, Eggo MC, Stewart PM. Regulation of 11 beta-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes.  J Endocrinol. 1998;  156 159-168
  • 36 Jamieson PM, Chapman KE, Edwards CR, Seckl JR. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11β-reductase in primary cultures of rat hepatocytes: Effect of physiochemical and hormonal manipulations.  Endocrinology. 1995;  136 4754-4761
  • 37 Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action.  Endocrinology. 1993;  132 2287-2292
  • 38 Renner E, Horber F, Jost G, Frey BM, Frey FJ. Effect of liver function on the metabolism of prednisone and prednisolone in humans.  Gastroenterology. 1986;  90 819-828
  • 39 Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker B. Tissue-specific dysregulation of cortisol metabolism in human obesity.  J Clin Endocrinol Metab. 2001;  86 1418-1421
  • 40 Moore JS, Monson JP, Kaltsas G, Putignano P, Wood PJ, Sheppard MC, Besser GM, Taylor NF, Stewart PM. Modulation of 11β-hydroxysteroid dehydrogenase isoenzymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.  J Clin Endocrinol Metab. 1999;  84 4172-4177
  • 41 Mauras N. Can growth hormone counteract the catabolic effects of steroids?.  Horm Res. 2009;  72 (S 01) 48-54
  • 42 Pralong FP, Miell JP, Corder R, Gaillard RC. Dexamethasone treatment in man induces changes in 24-hour growth hormone (GH) secretion profile without altering total GH released.  J Clin Endocrinol Metab. 1991;  73 1191-1196
  • 43 van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options?.  Eur J Clin Invest. 2009;  39 81-93
  • 44 Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ. Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice.  Proc Natl Acad Sci USA. 2004;  101 7088-7093
  • 45 Dötsch J, Rascher W. The role of 11β-hydroxysteroid dehydrogenase activity in the etabolic syndrome: lessons learned from the animal model.  Eur J Endocrinol. 2002;  146 603-605
  • 46 Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis.  Diabetes care. 2008;  31 2383-2390
  • 47 Gambertoglio JG, Vincenti F, Feduska NJ, Birnbaum J, Salvatierra Jr O, Amend WJ. Prednisolone disposition in cushingoid and non cushingoid kidney transplant patients.  J Clin Endocrinol Metab. 1980;  51 561-565
  • 48 Stewart PM, Boulton A, Kumar S, Clark PMS, Shackleton CHL. Cortisol metabolism in human obesity: impaired cortisone to cortisol conversion in subjects with central obesity.  J Clin Endocrinol Metab. 1999;  84 1022-1027
  • 49 Andrews RC, Herlihy O, Livingstone DE, Andrew R, Walker BR. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance.  J Clin Endocrinol Metab. 2002;  87 5587-5593

Correspondence

S. Diederich

Endokrinologikum Berlin am

Gendarmenmarkt

Centre for Endocrine and

Metabolism Diseases

Friedrichstraße 76 (Q207)

10117 Berlin

Phone: +49/30/2091 562 290

Fax: +49/30/2091 562 291

Email: sven.diederich@endokrinologikum.com

    >