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Horm Metab Res 2007; 39(8): 555-559
DOI: 10.1055/s-2007-984472
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Effect of Immunosuppressive and Other Drugs on the Cortisol-cortisone Shuttle in Human Kidney and Liver

M. Quinkler 1 , J. Jussli 2 , V. Bähr 2 , A. F. H. Pfeiffer 2 , J. Lepenies 3 , S. Diederich 2 , 4
  • 1Clinical Endocrinology, Department of Internal Medicine, Center for Gastroenterology, Heptology and Endocrinology, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 2Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 3Department of Nephrology, Campus Virchow, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 4Endokrinologikum Berlin, Berlin, Germany
Weitere Informationen

Publikationsverlauf

received 19.10.2006

accepted 15.02.2007

Publikationsdatum:
21. August 2007 (online)

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Abstract

Background: Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) has been suggested in patients with hypertension or renal disease, where it may contribute to sodium retention and hypertension. 11β-HSD1, which is expressed predominantly in liver and adipose tissue, influences glucose homeostasis and fat distribution by altering intracellular cortisol (F) concentrations. We tested immunosuppressive drugs that cause hypertension, and substances that interfere with steroidogenesis or influence glucose homeostasis for their ability to influence the inhibition of 11β-HSD isozymes.

Methods: For inhibition experiments, we used microsomes prepared from unaffected parts of human liver segments and resected human kidney cortex because of hepatocarcinoma or renal cell cancer. The inhibitory potency of several compounds was evaluated in concentrations from 10-9-10-5 mol/l.

Results: Only sirolimus, but not cyclosporine A, tacrolimus, mycophenolate mofetil, or azathioprine showed a slight inhibition of 11β-HSD2 activity. None of the drugs that inhibit steroidogenesis (suramine, mitotane, etomidate, and aminogluthethimide) or steroid metabolism (rifampicine) influenced 11β-HSDs, nor did ginsenoides Re, Rc, and Rb1. Among sulfonylureas, only gliclazide decreased significantly 11β-HSD1 activity.

Conclusions: Increased blood pressure due to immunosuppressive drugs is probably not caused by direct inhibition of 11β-HSD2. An additional glucose lowering effect of sulfonylurea gliclazide may be due to its ability to inhibit 11β-HSD1.

Key words

11β-hydroxysteroid - dehydrogenases - aldosterone - cortisol - drugs - obesity - sulfonylureas - mineralocorticoid receptor

References

  • 1 Tannin GM, Agarwal AK, Monder C, New MI, White PC. The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization.  J Biol Chem. 1991;  266 16653-16658
    PubMedGoogle Scholar
  • 2 Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11b-hydroxysteroid dehydrogenase type 2 enzyme.  Mol Cell Endocrinol. 1994;  105 R11-R17
    CrossrefPubMedGoogle Scholar
  • 3 Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.  Endocr Rev. 2004;  25 831-866
    CrossrefPubMedGoogle Scholar
  • 4 Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CRW, Seckl JR, Mullins JJ. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Nat Acad Sci USA. 1997;  94 14924-14929
    CrossrefPubMedGoogle Scholar
  • 5 Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.  Science. 1987;  237 268-275
    CrossrefPubMedGoogle Scholar
  • 6 Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.  Science. 1988;  242 583-585
    CrossrefPubMedGoogle Scholar
  • 7 Edwards CR, Stewart PM, Burt D, Brett L, MacIntyre MA, Sutanto WS, Kloet ER de, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase - tissue specific protector of the mineralocorticoid receptor.  Lancet. 1988;  2 986-989
    PubMedGoogle Scholar
  • 8 Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.  J Clin Invest. 1988;  82 340-349
    CrossrefPubMedGoogle Scholar
  • 9 Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle.  J Clin Endocrinol Metab. 2003;  88 2384-2392
    CrossrefPubMedGoogle Scholar
  • 10 Quinkler M, Zehnder D, Lepenies J, Petrelli MD, Moore JS, Hughes SV, Cockwell P, Hewison M, Stewart PM. Expression of renal 11beta-hydroxysteroid dehydrogenase type 2 is decreased in patients with impaired renal function.  Eur J Endocrinol. 2005;  153 291-299
    CrossrefPubMedGoogle Scholar
  • 11 Pretorius E, Wallner B, Marx J. Cortisol resistance in conditions such as asthma and the involvement of 11beta-HSD-2: a hypothesis.  Horm Metab Res. 2006;  38 368-376
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Quinkler M, Johanssen S, Grossmann C, Bahr V, Muller M, Oelkers W, Diederich S. Progesterone metabolism in the human kidney and inhibition of 11beta- hydroxysteroid dehydrogenase type 2 by progesterone and its metabolites.  J Clin Endocrinol Metab. 1999;  84 4165-4171
    CrossrefPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 Mariniello B, Ronconi V, Sardu C, Pagliericcio A, Galletti F, Strazzullo P, Palermo M, Boscaro M, Stewart PM, Mantero F, Giacchetti G. Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension.  Am J Hypertens. 2005;  18 1091-1098
    CrossrefPubMedGoogle Scholar
  • 15 Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus.  Clin Nephrol. 1998;  49 356-363
    PubMedGoogle Scholar
  • 16 Friemann S, Feuring E, Padberg W, Ernst W. Improvement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus.  Transplant Proc. 1998;  30 1240-1242
    CrossrefPubMedGoogle Scholar
  • 17 Feria I, Pichardo I, Juarez P, Ramirez V, Gonzalez MA, Uribe N, Garcia-Torres R, Lopez-Casillas F, Gamba G, Bobadilla NA. Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity.  Kidney Int. 2003;  63 43-52
    PubMedGoogle Scholar
  • 18 eppe CE, Heering PJ, Viengchareun S, Grabensee B, Farman N, Lombes M. Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor: a cell-based model to investigate partial aldosterone resistance in kidney transplantation.  Endocrinology. 2002;  143 1932-1941
    CrossrefPubMedGoogle Scholar
  • 19 Heering PJ, Kurschat C, Vo DT, Klein-Vehne N, Fehsel K, Ivens K. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression.  Clin Transplant. 2004;  18 186-192
    CrossrefPubMedGoogle Scholar
  • 20 Heering P, Grabensee B. Influence of ciclosporin A on renal tubular function after kidney transplantation.  Nephron. 1991;  59 66-70
    PubMedGoogle Scholar
  • 21 Julien J, Farge D, Kreft-Jais C, Guyene TT, Plouin PF, Houssin D, Carpentier A, Corvol P. Cyclosporine-induced stimulation of the renin-angiotensin system after liver and heart transplantation.  Transplantation. 1993;  56 885-891
    PubMedGoogle Scholar
  • 22 Ferrer-Martinez A, Felipe A, Barcelo P, Casado FJ, Ballarin J, Pastor-Anglada M. Effects of cyclosporine A on Na, K-ATPase expression in the renal epithelial cell line NBL-1.  Kidney Int. 1996;  50 1483-1489
    CrossrefPubMedGoogle Scholar
  • 23 Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review.  J Am Soc Nephrol. 1999;  10 1366-1380
    PubMedGoogle Scholar
  • 24 Schroth M, Plank C, Rauh M, Dorr HG, Rascher W, Dotsch J. Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure.  Eur J Endocrinol. 2006;  154 555-561
    CrossrefPubMedGoogle Scholar
  • 25 Lambert A, Frost J, Mitchell R, Wilson AU, Robertson WR. On the site of action of the anti-adrenal steroidogenic effect of etomidate and megestrol acetate.  Clin Endocrinol (Oxf). 1984;  21 721-727
    PubMedGoogle Scholar
  • 26 Preziosi P, Vacca M. Adrenocortical suppression and other endocrine effects of etomidate.  Life Sci. 1988;  42 477-489
    CrossrefPubMedGoogle Scholar
  • 27 Ayub M, Stitch SR. Effect of ketoconazole on placental aromatase, 3 beta-hydroxysteroid dehydrogenase-isomerase and 17 beta-hydroxysteroid dehydrogenase.  J Steroid Biochem. 1986;  25 981-984
    CrossrefPubMedGoogle Scholar
  • 28 Ashby H, DiMattina M, Linehan WM, Robertson CN, Queenan JT, Albertson BD. The inhibition of human adrenal steroidogenic enzyme activities by suramin.  J Clin Endocrinol Metab. 1989;  68 505-508
    PubMedGoogle Scholar
  • 29 Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma.  Clin Endocrinol (Oxf). 2004;  60 273-287
    CrossrefPubMedGoogle Scholar
  • 30 Macdonald IA, Roach PD. Bile induction of 7 alpha- and 7 beta-hydroxysteroid dehydrogenases in Clostridium absonum.  Biochim Biophys Acta. 1981;  665 262-269
    PubMedGoogle Scholar
  • 31 Salehi M, Ferenczi A, Zumoff B. Obesity and cortisol status.  Horm Metab Res. 2005;  37 193-197
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 32 Attele AS, Zhou YP, Xie JT, Wu JA, Zhang L, Dey L, Pugh W, Rue PA, Polonsky KS, Yuan CS. Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component.  Diabetes. 2002;  51 1851-1858
    CrossrefPubMedGoogle Scholar
  • 33 Chung SH, Choi CG, Park SH. Comparisons between white ginseng radix and rootlet for antidiabetic activity and mechanism in KKAy mice.  Arch Pharm Res. 2001;  24 214-218
    CrossrefPubMedGoogle Scholar
  • 34 Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus.  Drugs. 2004;  64 1339-1358
    CrossrefPubMedGoogle Scholar
  • 35 Muller G, Wied S. The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro.  Diabetes. 1993;  42 1852-1867
    PubMedGoogle Scholar
  • 36 Landstedt-Hallin L, Adamson U, Lins PE. Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes.  J Clin Endocrinol Metab. 1999;  84 3140-3145
    CrossrefPubMedGoogle Scholar
  • 37 ter Braak EW, Appelman AM, van dT, I, Erkelens DW, Haeften TW van. The sulfonylurea glyburide induces impairment of glucagon and growth hormone responses during mild insulin-induced hypoglycemia.  Diabetes Care. 2002;  25 107-112
    PubMedGoogle Scholar
  • 38 Glowka FK, Hermann TW, Zabel M. Bioavailability of gliclazide from some formulation tablets.  Intern J. Pharmaceutics. 1998;  172 71-77
    PubMedGoogle Scholar

Correspondence

M. QuinklerMD 

Division of Clinical Endocrinology

Department of Internal Medicine

Center for Gastroenterology

Hepatology and Endocrinology

Charité Campus Mitte

Charité Universitätsmedizin Berlin

Charitéplatz 1

10117 Berlin

Germany

Telefon: +49/30/45051 41 52

Fax: +49/30/45051 49 52

eMail: marcus.quinkler@charite.de

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