THE MOLECULAR MECHANISM OF THE ACTION OF THE PHARMACOLOGICAL DOSES OFGLUCOCORTICOIDS - STUDIES ON THE LOW-AFFINITY GLUCOCORTICOID RECEPTOR

The low-affinity glucocorticoid binding sites (LAGS, kDa 1-10 mu mol/L ) with glucocorticoid specificity were demonstrated in hepatic cytosol of rats. The induction of tyrosine aminotransferase (TAT) activity in primary cultures of rat hepatocytes by high concentration (10 mu mol/ L) of hydrocortisone (F) could be completely inhibited by RU486, the c ompetitive antagonist of glucocorticoid receptor, indicating that the induction of TAT by high concentrations of F is mediated by LAGS, ther efore, LAGS may be referred to as low-affinity glucocorticoid receptor (GR(L)). In order to study the effect of GC on GR(L), the concentrati on of glucocorticoids (GC) in plasma was maintained over 1 mu mol/L fo r 3 d by subcutaneous injection of F in polyvinyl alcohol into rats. T he binding capacity (Ro) of high-affinity glucocorticoid receptor (GR( H)) decreased significantly 1 h after injection and maintained at low level, whereas the Ro of GR(L) increased at 1, 24, and 48 h after inje ction. Thus, it may be concluded that GC can downregulate GR(H) but up regulate GR(L). These results strongly suggest that the action of phar macological doses of GC may be mediated by GR(L).