Early events in the action of glucocorticoids in developing tissues

Abstract

The interaction of glucocorticoids with developing tissues has been examined. Saturable, high affinity, glucocorticoid-specific binding sites (receptors) have been detected in several fetal and mature tissues of the rabbit and other species. Extensive studies in fetal rabbit lung indicate that nuclear uptake and retention of glucocorticoids in the tissue involves a multi-step mechanism in which the steroid first associates with an extranuclear receptor protein. Subsequently, the steroid-receptor complex is activated to a form which can enter the nucleus where it interacts with acceptor sites in the chromatin. The nuclear acceptor sites appear to involve DNA and do not seem to be specific for target tissues. Fetal lungs of various species contain glucocorticoid receptors long before the normal appearance of surfactant in alveolar spaces. In some species the pulmonary receptor could be detected only during fetal life suggesting a maturation-dependent responsiveness of lung to glucocorticoids. In addition to its ability to bind and retain glucocorticoids, the fetal rabbit lung is very efficient in activating cortisone to cortisol. Inactivation of cortisol to cortisone is a minor reaction. The failure of glucocorticoids to induce tyrosine aminotransferase in fetal rat liver does not appear to be due to the absence of receptors in this tissue. Glucocorticoid receptors are present in fetal rat liver and their concentration increases after birth reaching mature levels by the 5th postnatal day. A complex pattern of glucocorticoid interaction with adult liver nuclei was observed. Both high affinity and low affinity binding sites were detected. The high affinity sites do not appear to be homogeneous since only a small fraction is extractable with 0·4 M KCl. In addition, a fraction of these sites is released by Triton X-100 suggesting an interaction of glucocorticoids with nuclear membranes. In contrast, fetal rat liver nuclei appear to contain only a single class of high affinity sites and no evidence for the presence of low affinity sites or for glucocorticoid interaction with nuclear membranes was obtained. Comparative studies suggest that the glucocorticoid receptors of fetal and adult rat liver may not be identical. Evidence for this includes differences in the relative affinity of cortisol and corticosterone for the binding sites of fetal and adult liver cytosol as well as differences in the dissociation constants and sedimentation coefficients of the steroid-receptor complexes.