GLUCOCORTICOID RECEPTORS AND FLUTICASONE PROPIONATE

Glucocorticoid receptors are cellular signal transduction proteins, wh ich induce transcriptional modulation upon association with a corticos teroid ligand. New insights into the function and structure of recepto r domains, the composition and purpose of the nonactivated receptor pr otein assembly complex, and the activation and autoregulation of these receptors have been gained during recent years. In this review, the c linical relevance of ligand-induced receptor downregulation is discuss ed. Modulation of the glucocorticoid response by interfering signal tr ansduction pathways, activated by cellular mediators, environmental or therapeutic compounds, are summarized and assessed in relation to pot ential physiological or clinical significance. Glucocorticoid ligands with increasing potency have been developed, and among the various com pounds, fluticasone propionate deserves special attention. Fluticasone propionate is highly lipophilic due to a unique chemical substitution pattern which also leads to high selectivity and metabolic lability; it possesses the highest receptor affinity among glucocorticoids, impl ying fast association and slow dissociation from the receptor protein, and this explains the higher potency of fluticasone propionate and it s faster onset of clinical response compared to other corticosteroids. The receptor affinity of fluticasone propionate and the rank orders o f affinities of other corticosteroids are well correlated with the ind uction of anti-inflammatory responses on the cellular level as well as with the clinical efficacy of these compounds. Thus, since glucocorti coid responses are primarily receptor-mediated, the magnitude of their clinical effects and efficacy can be explained by the corticosteroids ' physicochemical properties which determine the glucocorticoid-recept or interactions.