[Medicinal activation and inhibition of function of glucocorticoid receptors as the basis for regulation of the glucocorticoid effect].
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On the basis of Scatchard and Lineweaver-Burk analysis, it was demonstrated that a series of drugs either activated or inhibited the function of types II and III glucocorticoid receptors. Analgine (0.04-10.0 mM) and sodium salicylate (12.5-50.0 mM) suppress the type II glucocorticoid receptor function of rat liver cytosol. Maradol (5.0 mM) increases the type II glucocorticoid receptors density but decreases the measurable constant for the [3H]acetonide triamsinolone interaction with type II glucocorticoid receptors. Analgine (1.25-10.0 mM) and sodium salicylate (0.62-10.0 mM) increase the type III glucocorticoid receptor function of rat liver cytosol. Maradol (0.25-1.0 mM) suppresses the type III glucocorticoid receptor function. The mechanism of regulation of the glucocorticoid effect by nonsteroid drugs influencing upon the function of types II and III glucocorticoid receptors is discussed.Keywords:
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Tyrosine aminotransferase
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Administration of corticosterone (10 mg/kg, ip, twice daily for 3 days) to mice during the second week of postnatal development led to an increase of tyrosine hydroxylase (TH) activity in the locus coeruleus, but not in the substantia nigra. The corticosterone effect was observed only transiently during this developmental period. Tritiated corticosterone can bind to a cytosol fraction prepared from mouse locus coeruleus, with a specific binding capacity of 110 fmol/mg protein. There is a correlation between the ability of various steroids to increase TH activity and their binding to the cytosol glucocorticoid receptor. Cortexolone and progesterone, two antiglucocorticoids that can bind to the cytosol receptor, were found to abolish the effect of corticosterone in increasing TH activity. It appears that the noradrenergic neurons in the locus coeruleus may be target cells for glucocorticoids, and that the glucocorticoid effect on TH may be by a receptor-mediated mechanism.
Locus coeruleus
Corticosterone
Tyrosine aminotransferase
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On the basis of Scatchard and Lineweaver-Burk analysis, it was demonstrated that a series of drugs either activated or inhibited the function of types II and III glucocorticoid receptors. Analgine (0.04-10.0 mM) and sodium salicylate (12.5-50.0 mM) suppress the type II glucocorticoid receptor function of rat liver cytosol. Maradol (5.0 mM) increases the type II glucocorticoid receptors density but decreases the measurable constant for the [3H]acetonide triamsinolone interaction with type II glucocorticoid receptors. Analgine (1.25-10.0 mM) and sodium salicylate (0.62-10.0 mM) increase the type III glucocorticoid receptor function of rat liver cytosol. Maradol (0.25-1.0 mM) suppresses the type III glucocorticoid receptor function. The mechanism of regulation of the glucocorticoid effect by nonsteroid drugs influencing upon the function of types II and III glucocorticoid receptors is discussed.
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As one step in characterizing the effectiveness of glucocorticoid hormones in states of abnormal carbohydrate metabolism, the number and affinity of glucocorticoid receptors in cytosolic extracts of liver and kidney from ob/ob mice and pancreata from streptozotocin-treated rats were determined and compared to values derived from normals. Scatchard analysis revealed that each tissue contained the same number of glucocorticoid receptors as its control when expressed in terms of receptor number per mg of cytosolic protein. Similarly, the affinity of these receptors for dexamethasone was unchanged. It is concluded that these two forms of diabetes are not associated with abnormalities of glucocorticoid receptor number.
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Stereoselective competition was used to determine (3H)-aldosterone binding to type I corticosteroid receptors, and (3H)-dexamethasone binding to type II receptors in punches obtained from 11 brain regions of short-term adrenalectomized (ADX) rats. It was observed that type I receptor binding was almost exclusive of the hippocampus (HIPPO), while type II receptor binding was more generally distributed among HIPPO, cerebral cortex, lateral septum, ventromedial and arcuate hypothalamic nuclei, with lower levels in 6 additional regions studied. We determined corticosterone (CORT) in brain punches from ADX rats, ADX rats receiving CORT for 5 days, intact rats and intact rats receiving ACTH for 5 days. We correlated (3H)-ligand binding with CORT content in punches obtained from identical brain regions and showed a significant positive correlation in the case of the ADX plus CORT group, for type II corticosteroid receptors. Similarly, a significant correlation emerged with type II sites, when binding capacity was correlated with percentage increases of CORT in brain areas of rats receiving ACTH. It is suggested that in situations where CORT levels are elevated, changes in CORT retention throughout the brain occur as a function of the type II glucocorticoid receptor, although at the level of the HIPPO, both receptors may provide appropriate control of the CNS-pituitary-adrenal axis, according to the physiological or stress levels of circulating hormone.
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Using a charcoal technique, we determined the relative binding affinity of some anabolic compounds for the androgen and glucocorticoid receptors in cytosol from rat skeletal muscle. Only a few of the compounds analyzed competed for the receptor-binding sites. The androgen and glucocorticoid receptors were analyzed in rat and mouse skeletal muscle cytosols by Scatchard analysis. In rats grouped according to sex and age, the cytosolic protein content was about the same in all groups, but the DNA content decreased with increased weight of the animal regardless of sex (male, female, or castrated male). The glucocorticoid receptor did not differ in concentration (2–3 pmol/g tissue) or ligand affinity (Kd, 10–40 nM) among the groups, but the androgen receptor concentration decreased with increased weight and age of the animals, more in the case of males than in the case of females or castrates. The Kd for the androgen receptor increased with age in males but was constantly about 0.2 nM for castrates or females. In adult intact rats, the androgen and glucocorticoid receptor concentrations in muscle cytosol from females were about 100 and 3000 fmol/g tissue, respectively, the corresponding values for males being about 50 and 2000 fmol/g tissue, respectively. Short term castration or adrenalectomy increased the concentration of and ligand affinity for the androgen and glucocorticoid receptors, respectively. After long term castration of male rats, the concentration of both receptors increased during 5 weeks to about the female level, only to decrease later. Neonatally castrated male rats had about the same androgen receptor concentrations and Kd values as female rats. Female mice had higher androgen receptor concentrations (∼700 fmol/g tissue) than rats. Intact male mice had about 200 fmol androgen receptor-binding sites/g tissue, and the same amount was found in mice bearing the testicular feminization (Tfm) mutant gene. In summary, the concentrations of androgen and glucocorticoid receptors in rat skeletal muscle are regulated at least by the testes. The presence of androgen receptors in skeletal muscle from Tfm mice is surprising and may motivate a reinvestigation of the regulation of androgen receptors in Tfm animals.
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Some glucocorticoid-inducible hepatic enzymes fail to respond to hormone administration prenatally but do respond soon after birth. One possible mechanism for this lack of responsivity is incomplete development of the glucocorticoid receptor system in the fetus. To evaluate this hypothesis, 3H-dexamethasone binding was studied in vitro in liver cytosol from fetuses (days 19–20) and young rats (days 1–29). Glucocorticoid receptors are present as early as days 19–20 of gestation and resemble adult receptors in affinity for 3H-dexamethasone and specificity for other steroid hormones. By Scatchard analysis the concentration of receptors is lower in the fetus (0.11 pmoles/mg cytosol protein) than at any postpartum date studied (0.26–0.55). However, since only unoccupied receptors are detected by the assay, this apparent difference in receptor concentration is felt to be the result of elevated levels of endogenous corticosterone in the fetus (37.8 μg/100 ml) compared to young rats (1.3–6.4 μg/100 ml). The fetal receptors are functional by the criterion of nuclear transfer of 3H-dexamethasone. Although glucagon administration o t the fetus has been shown to result in precocious development of some glucocorticoid-inducible hepatic enzymes, no significant change in receptor affinity or concentration is found after such treatment. The findings suggest that the fetal glucocor-ticoid receptors are intact and that the failure of prenatal glucocorticoid to result in enzyme induction is probably due to a block distal to the nuclear uptake step. (Endocrinology95: 1219, 1974)
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The present investigation was undertaken to define the developmental pattern of glucocorticoid binding to the anterior pituitary gland and ascertain whether that binding correlated to modulation of corticotropin-releasing factor-induced release of ACTH. Scatchard analysis of data revealed the presence in cytosol (besides classical receptor sites interacting with both [3H]dexamethasone and [3H]corticosterone) of a transcortin-like component binding only the natural steroid. Whereas the number of sites of the former binder was not significantly altered during maturation and remained close to the adult value (276± 12 fmol/mg protein), that of the latter declined dramatically after birth and rose again after postnatal day 10. The apparent Kd, however, remained unchanged. Transfer of the [3H]dexamethasone-receptor complex to nuclei of pituitary cells from neonates 2–6 days of age was found to be 20% that of adults despite the presence of comparable concentrations of receptor sites. Mixing experiments carried out with cytosol and nuclear fractions from different origins pointed to the cytoplasmic compartment as being implicated in this discrepancy. It was not until after postnatal day 10 that nuclear transfer reached mature levels. Although the extent of nuclear uptake and the magnitude of inhibition of ACTH secretion, as judged by means of a perifusion system, correlated well in hypophyses from 10- to 30-day-old neonates and adults, steroid binding and induction of biological response at earlier time points ere less closely related. The results indicate the existence during development of a transient dissociation between cytosol and nuclear binding of corticosteroids by the anterior pituitary as well as between the latter process and blockade of ACTH release. These data are discussed in connection with the postnatal period nonresponsive to stress. (Endocrinology108: 591, 1981)
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