Receptor dynamics and tyrosine aminotransferase induction during the course of chronic treatment of rats with glucocorticoid.

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Abstract
The changes in the cytosol glucocorticoid receptor (GR) content during a long-term administration of a glucocorticoid were studied to examine the mechanism of the development of steroid hormone resistance. Dexamethasone (Dex)(0.2 .mu.g ml and 2.0 .mu.g/ml) was given to adrenalectomized rats, and the GR content was determined using the exchange assay 1, 10, 20 and 50 days after the start of administration. The activity of tyrosine aminotransferase (TAT) in the cytosol was also assayed as a measure of the biological responsiveness of these animals to the administered glucocorticoid. The dissociation constant (Kd) was elevated and the Bmaxs of the GR in the cytosol were decreased by the lower concentration of Dex. The Bmaxs decreased to 30% of the untreated controls within 24 h and this lower level was maintained as long as the hormone treatment continued. On the other hand, the cytosol obtained from animals treated with 2.0 .mu.g/ml of Dex for 20-24 days did not show any measurable amount of binding to 3H-Dex. The activity of TAT was elevated 24 h after the administration of Dex but decreased gradually and steadily with time during the experimental period. To examine the biological potency of remaining GR in the liver cytosol, 2.0 .mu.g/ml Dex was again administered after a long-term treatment. This treatment eliminated the remaining GR completely and induced TAT at almost the same rate as observed in the untreated control animals. The pattern of depletion and replenishment of the GR after single injection of hydrocortisone in the animals that had received 20 .mu.g/ml Dex for 14 days followed by steroid free drinking fluid for 3 days was also determined and compared with those of the untreated control. No significant differences were observed between the two animal groups in the kinetics of depletion or replenishment of the GR. We concluded that the function of GR in the Rat liver was not distorted significantly during the course of the long-term Dex treatment.