The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation

Toxicological Sciences

Volumn 126, Issue 2, 2012, Pages 353-361

  Fürstenberger, Cornelia ^a   Vuorinen, Anna ^b   Da cunha, Thierry ^a   Kratschmar, Denise V ^a   Saugy, Martial ^c,d   Schuster, Daniela ^b   Odermatt, Alex ^a  

^a UNIVERSITY OF BASEL   (Switzerland)

^b UNIVERSITY OF INNSBRUCK   (Austria)

^c UNIVERSITY CENTER OF LEGAL MEDICINE   (Switzerland)

^d LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

Author keywords

11 hydroxysteroid dehydrogenase; Anabolic androgenic steroid; Cardiovascular disease; Fluoxymesterone; Glucocorticoid; Hypertension; Testosterone

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 2; DANAZOL; FLUOXYMESTERONE; FORMEBOLONE; GLUCOCORTICOID; GLYCYRRHETINIC ACID; HYDROCORTISONE; MESTEROLONE; METENOLONE; NORBOLETONE; OXYMESTERONE; OXYMETHOLONE; PRASTERONE; TESTOSTERONE;

ANIMAL CELL; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CELL LYSATE; CELL STRAIN MCF 7; CONTROLLED STUDY; DRUG BINDING; DRUG EFFECT; DRUG METABOLISM; DRUG POTENCY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; KIDNEY MICROSOME; MALE; NONHUMAN; RAT; STEROID BINDING;

MUS; RATTUS;

EID: 84859029706     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfs022     Document Type: Article

References (41)

1. Ansell, J. E., Tiarks, C., and Fairchild, V. K. (1993). Coagulation abnormalities associated with the use of anabolic steroids. Am. Heart J. 125, 367-371.
2. Basaria, S. (2010). Androgen abuse in athletes: Detection and consequences. J. Clin. Endocrinol. Metab. 95, 1533-1543.
3. Briet, M., and Schiffrin, E. L. (2010). Aldosterone: Effects on the kidney and cardiovascular system. Nat. Rev. Nephrol. 6, 261-273.
4. Buckley, W. E., Yesalis, C. E., III, Friedl, K. E., Anderson, W. A., Streit, A. L., and Wright, J. E. (1988). Estimated prevalence of anabolic steroid use among male high school seniors. J. Am. Med. Assoc. 260, 3441-3445.
5. Calof,O.M., Singh,A. B., Lee,M. L., Kenny, A. M.,Urban, R. J., Tenover, J. L., and Bhasin, S. (2005). Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebocontrolled trials. J. Gerontol. A Biol. Sci. Med. Sci. 60, 1451-1457.
6. Caprio, M., Newfell, B. G., la Sala, A., Baur, W., Fabbri, A., Rosano, G., Mendelsohn, M. E., and Jaffe, I. Z. (2008). Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ. Res. 102, 1359-1367.
7. D'Andrea, A., Caso, P., Salerno, G., Scarafile, R., De Corato, G., Mita, C., Di Salvo, G., Severino, S., Cuomo, S., Liccardo, B., et al. (2007). Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: A Doppler myocardial and strain imaging analysis. Br. J. Sports Med. 41, 149-155.
8. Deuchar, G. A., McLean, D., Hadoke, P. W., Brownstein, D. G., Webb, D. J., Mullins, J. J., Chapman, K., Seckl, J. R., and Kotelevtsev, Y. V. (2011). 11beta-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe-/-mice. Endocrinology 152, 236-246.
9. Ferrari, P. (2010). The role of 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim. Biophys. Acta 1802, 1178-1187.
10. Ferrari, P., Sansonnens, A., Dick, B., and Frey, F. J. (2001). In vivo 11beta-HSD-2 activity: Variability, salt-sensitivity, and effect of licorice. Hypertension 38, 1330-1336.
11. Frey, F. J., Odermatt, A., and Frey, B. M. (2004). Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr. Opin. Nephrol. Hypertens. 13, 451-458.
12. Gaware, R., Khunt, R., Czollner, L., Stanetty, C., Da Cunha, T., Kratschmar, D. V., Odermatt, A., Kosma, P., Jordis, U., and Classen-Houben, D. (2011). Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11beta-hydroxysteroid dehydrogenase 2 inhibitors. Bioorg. Med. Chem. 19, 1866-1880.
13. Glazer, G. (1991). Atherogenic effects of anabolic steroids on serum lipid levels. A literature review. Arch. Intern. Med. 151, 1925-1933.
14. Goodwin, J. E., Zhang, J., and Geller, D. S. (2008). A critical role for vascular smooth muscle in acute glucocorticoid-induced hypertension. J. Am. Soc. Nephrol. 19, 1291-1299.
15. Hadoke, P. W., Iqbal, J., and Walker, B. R. (2009). Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br. J. Pharmacol. 156, 689-712.
16. Hall, R. C. (2005). Abuse of supraphysiologic doses of anabolic steroids. South. Med. J. 98, 550-555.
17. Handelsman, D. J. (2011). Androgen misuse and abuse. Best Pract. Res. Clin. Endocrinol. Metab. 25, 377-389.
18. Jones, G., Willett, P., Glen, R. C., Leach, A. R., and Taylor, R. (1997). Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267, 727-748.
19. Kanayama, G., Brower, K. J., Wood, R. I., Hudson, J. I., and Pope, H. G., Jr (2009). Anabolic-androgenic steroid dependence: An emerging disorder. Addiction 104, 1966-1978.
20. Klusonova, P., Rehakova, L., Borchert, G., Vagnerova, K., Neckar, J., Ergang, P., Miksik, I., Kolar, F., and Pacha, J. (2009). Chronic intermittent hypoxia induces 11beta-hydroxysteroid dehydrogenase in rat heart. Endocrinology 150, 4270-4277.
21. Kratschmar, D. V., Vuorinen, A., Da Cunha, T., Wolber, G., Classen-Houben, D., Doblhoff, O., Schuster, D., and Odermatt, A. (2011). Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11beta-hydroxysteroid dehydrogenase type 2. J. Steroid Biochem. Mol. Biol. 125, 129-142.
22. Kuhn, C. M. (2002). Anabolic steroids. Recent Prog. Horm. Res. 57, 411-434.
23. Lastra, G., Dhuper, S., Johnson, M. S., and Sowers, J. R. (2010). Salt, aldosterone, and insulin resistance: Impact on the cardiovascular system. Nat. Rev. Nephrol. 7, 577-584.
24. Naray-Fejes-Toth, A., and Fejes-Toth, G. (2007). Novel mouse strain with Cre recombinase in 11beta-hydroxysteroid dehydrogenase-2-expressing cells. Am. J. Physiol. Renal. Physiol. 292, F486-F494.
25. Odermatt, A., and Atanasov, A. G. (2009). Mineralocorticoid receptors: Emerging complexity and functional diversity. Steroids 74, 163-171.
26. Odermatt, A., and Kratschmar, D. V. (2012). Tissue-specific modulation of mineralocorticoid receptor function by 11beta-hydroxysteroid dehydrogenases: An overview. Mol. Cell. Endocrinol. 350, 168-186.
27. Parr, M. K., and Schanzer, W. (2010). Detection of the misuse of steroids in doping control. J. Steroid Biochem. Mol. Biol. 121, 528-537.
28. Parssinen, M., Kujala, U., Vartiainen, E., Sarna, S., and Seppala, T. (2000). Increased premature mortality of competitive powerlifters suspected to have used anabolic agents. Int. J. Sports Med. 21, 225-227.
29. Pitt, B., Reichek, N., Willenbrock, R., Zannad, F., Phillips, R. A., Roniker, B., Kleiman, J., Krause, S., Burns, D., and Williams, G. H. (2003a). Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: The 4E-left ventricular hypertrophy study. Circulation 108, 1831-1838.
30. Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B., Bittman, R., Hurley, S., Kleiman, J., and Gatlin, M. (2003b). Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309-1321.
31. Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., Palensky, J., and Wittes, J. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341, 709-717.
32. Pozo, O. J., Van Thuyne, W., Deventer, K., Van Eenoo, P., and Delbeke, F. T. (2008). Elucidation of urinary metabolites of fluoxymesterone by liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. J. Mass Spectrom. 43, 394-408.
33. Rebuffat, A. G., Tam, S., Nawrocki, A. R., Baker, M. E., Frey, B. M., Frey, F. J., and Odermatt, A. (2004). The 11-ketosteroid 11-ketodexamethasone is a glucocorticoid receptor agonist. Mol. Cell. Endocrinol. 214, 27-37.
34. Schweizer, R. A., Atanasov, A. G., Frey, B. M., and Odermatt, A. (2003). A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): Flavanone selectively inhibits 11beta-HSD1 reductase activity. Mol. Cell. Endocrinol. 212, 41-49.
35. Senesi, S., Legeza, B., Balazs, Z., Csala, M., Marcolongo, P., Kereszturi, E., Szelenyi, P., Egger, C., Fulceri, R., Mandl, J., et al. (2010). Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: Possible implication in the metabolic syndrome. Endocrinology 151, 4830-4839.
36. Serra, A., Uehlinger, D. E., Ferrari, P., Dick, B., Frey, B. M., Frey, F. J., and Vogt, B. (2002). Glycyrrhetinic acid decreases plasma potassium concentrations in patients with anuria. J. Am. Soc. Nephrol. 13, 191-196.
37. Sullivan, M. L., Martinez, C. M., Gennis, P., and Gallagher, E. J. (1998). The cardiac toxicity of anabolic steroids. Prog. Cardiovasc. Dis. 41, 1-15.
38. Thompson, P. D., Cullinane, E. M., Sady, S. P., Chenevert, C., Saritelli, A. L., Sady, M. A., and Herbert, P. N. (1989). Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. J. Am. Med. Assoc. 261, 1165-1168.
39. Verdonk, M. L., Cole, J. C., Hartshorn, M. J., Murray, C. W., and Taylor, R. D. (2003). Improved protein-ligand docking using GOLD. Proteins 52, 609-623.
40. Wolber, G., and Langer, T. (2005). LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model. 45, 160-169.
41. Yesalis, C. E., Barsukiewicz, C. K., Kopstein, A. N., and Bahrke, M. S. (1997). Trends in anabolic-androgenic steroid use among adolescents. Arch. Pediatr. Adolesc. Med. 151, 1197-1206.