Endocrinology, Vol 130, 430-436, Copyright © 1992 by Endocrine Society

ARTICLES

Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter

B Couette, V Marsaud, EE Baulieu, H Richard-Foy and ME Rafestin-Oblin
Unite de Recherches sur les Communications Hormonales, INSERM U 33, Bicetre, France.

The ability of the glucocorticosteroid receptor to bind mineralocorticosteroids suggests that spironolactone, a potent aldosterone antagonist, may also interact with the glucocorticosteroid receptor, resulting in an agonist or antagonist glucocorticosteroid activity. We have investigated the effect of this drug on the activity of the glucocorticosteroid-regulated mouse mammary tumor virus (MMTV) promoter. For these studies we used the mouse fibroblast cell line 1471.1. It contains about 200 copies of a permanently established chimeric DNA construct comprising a transcription unit [MMTV long terminal repeat (LTR)] driving the reporter gene chloramphenicol acetyltransferase linked to the 69% transforming fragment of the bovine papilloma virus genome. This cell line has a high level of glucocorticosteroid receptor (1200 fmol/mg protein) and no detectable mineralocorticosteroid receptor. Competition experiments showed a binding of spironolactone to glucocorticosteroid receptor, with an affinity 50-fold lower than that of dexamethasone. In these cells, spironolactone behaves as an antiglucocorticosteroid, inhibiting in a dose-dependent fashion dexamethasone-induced chloramphenicol acetyltransferase activity, with an ED50 of 8 microM. The absence of agonist activity, even at a high concentration of this compound (10 microM), demonstrates that spironolactone is a pure antiglucocorticosteroid in this cell line. MMTV LTR DNase-I hypersensitivity studies demonstrated that spironolactone, when administered in combination with dexamethasone, inhibits formation of the hormone-induced hypersensitive site located about 160 basepairs up- stream of the MMTV cap site. Furthermore, spironolactone alone failed to induce this DNase-I-hypersensitive site, suggesting that the antagonist-receptor complex does not interact productively with MMTV LTR chromatin.

This article has been cited by other articles:

				V. Gupta, N. Awasthi, and B. J. Wagner Specific Activation of the Glucocorticoid Receptor and Modulation of Signal Transduction Pathways in Human Lens Epithelial Cells Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1724 - 1734. [Abstract] [Full Text] [PDF]

				C. Boixel, B. Gavillet, J.-S. Rougier, and H. Abriel Aldosterone increases voltage-gated sodium current in ventricular myocytes Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2257 - H2266. [Abstract] [Full Text] [PDF]

				K. Lister, D. J. Autelitano, A. Jenkins, R. D. Hannan, and K. E. Sheppard Cross talk between corticosteroids and alpha-adrenergic signalling augments cardiomyocyte hypertrophy: A possible role for SGK1 Cardiovasc Res, June 1, 2006; 70(3): 555 - 565. [Abstract] [Full Text] [PDF]

				J. Zschocke, N. Bayatti, A. M. Clement, H. Witan, M. Figiel, J. Engele, and C. Behl Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions J. Biol. Chem., October 14, 2005; 280(41): 34924 - 34932. [Abstract] [Full Text] [PDF]

				S. R. Pondugula, J. D. Sanneman, P. Wangemann, P. G. Milhaud, and D. C. Marcus Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1127 - F1135. [Abstract] [Full Text] [PDF]

				P. Sawathiparnich, S. Kumar, D. E. Vaughan, and N. J. Brown Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 448 - 452. [Abstract] [Full Text] [PDF]

				K. E. Sheppard and D. J. Autelitano 11{beta}-Hydroxysteroid Dehydrogenase 1 Transforms 11-Dehydrocorticosterone into Transcriptionally Active Glucocorticoid in Neonatal Rat Heart Endocrinology, January 1, 2002; 143(1): 198 - 204. [Abstract] [Full Text] [PDF]