Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.

We characterized the pharmacological profiles of the human mineralocorticoid and glucocorticoid receptor for 11 natural and synthetic steroids regarding binding pharmacology, intracellular localization of hormone-receptor complexes, and agonistic or antagonistic properties at the gene expression level. The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. These results are supported by immunofluorescence studies, in which both unliganded human mineralocorticoid and glucocorticoid receptors were distributed throughout the cytoplasm and nucleus, whereas agonist- as well as antagonist-receptor complexes showed an exclusively nuclear localization. These results contribute to the understanding of antihormone pharmacology and increase our understanding of the role of human mineralocorticoid and glucocorticoid receptors in physiological processes during different endocrine states.