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PubMed1984

Intracellular CBG-like molecules in the rat pituitary.

The localization of transcortin (CBG) in pituitary cells of the rat was investigated using the peroxydase-antiperoxydase (PAP) technique. A rabbit antiserum against purified rat plasma transcortin was used as the primary antiserum. Transcortin-like (CBG-like) immunoreactive products were found in the cytoplasma of certain cells in the anterior pituitary, but not in the intermediate lobe and weakly in the posterior pituitary. It is postulated that the CBG-like molecules participate in the cellular uptake process of corticosterone, thereby modulating the feedback signal of this steroid on pituitary function.

Animals↗

PubMed1986

Transport and intracellular localization of cortisol-asialotranscortin complexes in rat liver.

The influence of desialylation of human transcortin on transport of the transcortin-cortisol complex into the liver cells and its intracellular distribution was investigated in perfused rat liver. Under experimental conditions used the half-time of cortisol in perfusion medium was decreased more than 200 times in presence of asialotranscortin compared to that of native transcortin. Experiments with [3H]cortisol and [131I]asialotranscortin demonstrated a simultaneous uptake of cortisol and asialotranscortin by the hepatocytes. Distribution of [3H]cortisol and [131I]asialotranscortin in subcellular fractions showed the following pathway of cortisol-asialotranscortin complex: cell membrane, lysosomes, cytoplasm. The complex dissociates in lysosomes.

Animals↗

PubMed1981

Effect of oestriol, oestradiol valerate and ethinyloestradiol on serum proteins in oestrogen-deficient women.

The effect of oestriol (3 mg for 3 mth), oestradiol valerate (2 mg for 3 mth) and ethinyloestradiol (0.025 mg for 21 days) on sex hormone binding globulin (SHBG), transcortin, ceruloplasmin and pregnancy-associated macro-globulin (PAG) was analysed in oestrogen-deficient women. The doses of oestrogens were therapeutically effective for the treatment of oestrogen-deficiency symptoms. Treatment with 0.025 mg ethinyloestradiol induced a 281% increase in PAG, a 119% increase in SHBG, a 74% increase in transcortin and a 74% increase in ceruloplasmin levels. Administration of 2 mg oestradiol valerate resulted in a 40% increase in SHBG, a small increase in transcortin and ceruloplasmin, whereas PAG levels remained unaffected. None of the parameters tested were affected by oestriol treatment. PAG was clearly the most sensitive parameter for ethinyloestradiol while SHBG was the most sensitive parameter for oestradiol valerate. These results show no relationship between clinical efficacy and effect of plasma protein synthesis, and demonstrate that one has to be very careful when comparing potency estimates for different oestrogens and different parameters.

Adult↗

PubMed1984

Altered plasma protein-binding of prednisolone in patients with the nephrotic syndrome.

Prednisolone binds in plasma to both albumin and transcortin. Since altered concentrations of plasma proteins change capacity and association constants of the drug-protein complex and thus influence the disposition of the drug, the kinetics of prednisolone following oral prednisone and intravenous (IV) prednisolone were studied in ten nephrotic patients and in 12 healthy volunteers. Compared to normal volunteers, nephrotic patients had significantly higher mean (+/- SD) association constants for the albumin-prednisolone complex (4.20 +/- 2.10 X 10(3) M-1 v 2.26 +/- 0.46 X 10(3) M-1, P less than 0.005) and tended to have higher association constants for the transcortin-prednisolone complex. Following the IV administration of prednisolone and the oral administration of prednisone, nephrotic patients exhibited lower total plasma concentrations of prednisolone than did normal volunteers. The difference was attributable to lower albumin-bound and/or transcortin-bound, but not unbound, concentrations of prednisolone in plasma. The mean prednisolone bioavailability from oral prednisone was not different between nephrotic patients and controls. When calculated with reference to total prednisolone concentrations in plasma, the mean nonrenal clearance rate, but not the mean renal clearance rate, was higher in the nephrotic patients than in the controls (2.63 +/- 0.61 mL/min/kg v 1.85 +/- 0.33 mL/min/kg, P less than 0.005). Compared to normal volunteers, patients with the nephrotic syndrome had lower renal clearance rates of unbound prednisolone when prednisolone was given intravenously (1.58 +/- 0.88 mL/min/kg v 2.89 +/- 0.89 mL/min/kg, P less than 0.005) or when prednisone was given orally (1.18 +/- 0.86 mL/min/kg v 2.80 +/- 1.13 mL/min/kg, P less than 0.005). Nephrotic patients had lower ratios of unbound prednisolone clearance/creatinine clearance (fractional excretion) after IV prednisolone (1.50 +/- 0.81 v 2.27 +/- 0.49, P less than 0.025) or after oral prednisone (1.07 +/- 0.60 v 2.12 +/- 0.77, P less than 0.005) than the controls. Since these fractional excretion values of unbound prednisolone exceeded one, there must be glomerular filtration of prednisolone bound to plasma proteins and/or tubular secretion of prednisolone. This study indicates that the nephrotic dysproteinemia changes the binding of prednisolone to plasma proteins not only in point of quantity, but also in point of quality, and alters the disposition of prednisolone.

Administration, Oral↗

PubMed1982

Rat anterior pituitary. Distinction of an approximately 8S, corticosterone-preferring species from dexamethasone-binding glucocorticoid receptors.

Studies on the feedback inhibition of ACTH release by steroid hormones and on the binding of tritiated steroids by the pituitary have prompted the hypothesis that receptors in addition to or other than classical glucocorticoid receptors may mediate steroid hormone effects in this tissue. Accordingly, we have asked whether more than one glucocorticoid-binding species, distinct from corticosteroid binding globulin, can be found in rat anterior pituitary gland. In our study we have demonstrated high affinity (K(d) 4 degrees C approximately 1 nM) binding sites for tritiated corticosterone ((3)H-B) in rat pituitary cytosol, distinct from classical glucocorticoid receptors and transcortin-like sites. Unlike (3)H-B-transcortin complexes, (3)H-B bound to such sites is adsorbed onto hydroxylapatite and is stabilized by sulphydryl group reducing agents. Sucrose density gradient analysis in low ionic strength buffer under equilibrium conditions ((3)H-B+/-nonradioactive competitors throughout) showed (3)H-B to sediment as a single, approximately 8S peak, from which (3)H-B was consistently better displaced by B than dexamethasone (DM); (3)H-DM similarly bound to an approximately 8S peak, from which it was better displaced by DM than B. The existence of two species of pituitary glucocorticoid receptors is further supported by clear differences in specificity for a range of steroids, and in the differential depletion of cytoplasmic sites after in vivo DM administration. Similar "B-preferring" sites were not found in thymus cytosols. These results demonstrate that there exist in the pituitary high affinity intracellular binding sites for naturally occurring glucocorticoids, distinct from classical glucocorticoid receptors and transcortin-like sites. Physiological roles as glucocorticoid receptors remain to be established for these B-preferring sites.

Animals↗

PubMed1976

Increased plasma protein binding and lower metabolic clearance rate of aldosterone in plasma of low cortisol concentration.

During ACTH or cortisol infusion in ten recumbent normal men taking dexamethasone, the metabolic clearance rate of aldosterone increased by 50% as plasma cortisol was raised from low (2 mug/dl) to high concentration (50 mug/dl). Since splanchnic blood flow did not change, a greater efficiency of removal of aldosterone must have occurred, by means of displacement of aldosterone from high-affinity sites on plasma protein. At 37 C, equilibrium dialysis of low-cortisol plasma showed one-third of plasma aldosterone bound to albumin, and 24 to 28% bound to higher-affinity sites on other protein. As plasma cortisol increased, a progressively smaller fraction was tightly bound, approaching zero as transcortin was saturated with cortisol. The addition of large amounts of aldosterone to low-cortisol plasma displaced 14C-cortisol from transcortin binding sites. The results support earlier evidence that a significant fraction of plasma aldosterone is bound to transcortin, from which it is readily displaced by cortisol, resulting in an increased metabolic clearance rate of aldosterone by making a larger fraction available for removal from plasma.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

[Hormone-protein interactions and functional activity of the adrenal cortex during adaptation to pressure chamber hypoxia].

Blood plasma and adrenals of rats subjected to the exposure of deep pressure-chamber hypoxia are studied. The method of high-performance liquid chromatography is used to determine the content of corticosterone and deoxycorticosterone as well as the binding ability of transcortin relative to hydrocortisone and corticosterone before and after ectomy of endogenic hormones. It is shown that hyperactivation of adrenals occurs already the first 20 min of the experiment, which is preserved during the whole experiment lowering, to some extent, by 150, 240 min. The binding ability of transcortin considerably lowers in the acute phase of stress and after the prolonged hypoxic exposure due to a 1.5-1.9-fold decrease in the number of the binding sites in the protein. The equilibrium redistribution is revealed in the plasma between free corticosterone and corticosterone bound to transcortin at the different stages of the hypoxic exposure.

Adaptation, Physiological↗

PubMed1987

[Transport and intracellular distribution of components of the cortisol-asialotranscortin complex in the liver].

The effect of desialation of human transcortin on the transcortin-cortisol complex transport into hepatocytes and on subsequent intracellular distribution of the complex components was studied in model experiments with perfused rat liver. It was demonstrated that in the presence of desialated transcortin the time of [3H]cortisol incubation in the perfusion medium decreased more than 200 times as compared with the native protein. [3H]cortisol and [131I]asialotranscortin trapping by hepatocytes occurs simultaneously. The content of the [3H]cortisol--[131I]asialotranscortin complex in rat liver plasma membranes reaches a maximum 3 min after beginning of perfusion. Then the intact complex is transported into lysosomes, where it dissociates with a subsequent release of asialotranscortin and cortisol metabolites into the cytoplasm.

Animals↗

PubMed1986

Methylprednisolone versus prednisolone pharmacokinetics in relation to dose in adults.

The disposition and plasma binding of methylprednisolone were examined in seven normal volunteers following the administration of 5, 20 and 40 mg of intravenous methylprednisolone sodium succinate. Methylprednisolone exhibits linear plasma protein binding averaging 77%. The mean plasma methylprednisolone clearance of 337 ml X h-1 X kg-1 was independent of dose. The steroid appears to moderately distribute into tissue spaces with a mean volume of distribution of 1.41 X kg-1. Methylprednisolone disposition parameters were compared with the non-transcortin bound parameters for prednisolone. The prednisolone plasma clearance based on the transcortin free-drug is similar to methylprednisolone total plasma clearance. However, the corrected volume of distribution of prednisolone is only one-half that of methylprednisolone. The disposition rate of these two steroids is thus similar, in spite of their metabolic control by different enzymatic pathways and major influence of saturable transcortin binding on prednisolone elimination.

Adult↗

PubMed1989

A comparison between the composition of maternal peripheral plasma and plasma collected from the retroplacental compartment at caesarean section. A study on protein and steroid hormones and binding proteins.

In the pregnant uterus unique immunological conditions must prevail. Since compounds of possible fetoplacental origin may modulate the local maternal immunological response, higher concentrations of such compounds in the vicinity of the conceptus might be expected. We have measured the concentrations of several compounds in peripheral and retroplacental plasma, mainly by immunological methods, from women delivered by caesarean section in pregnancy week 38-40. Significantly higher (P less than 0.001) retroplacental concentrations were found for human placental lactogen, prolactin, alpha-fetoprotein, tissue polypeptide antigen, non-conjugated estriol and progesterone. Peripheral plasma levels were significantly higher for cortisol (P less than 0.01), transcortin (P less than 0.001) and sex-hormone binding globulin (P less than 0.002). No difference was found for albumin, alpha 2-macroglobulin, estradiol, placental alkaline phosphatase and human chorionic gonadotrophin. Significant correlations between retroplacental and maternal peripheral plasma levels were found for progesterone, cortisol, estradiol, estriol, transcortin, sex-hormone binding globulin, prolactin, human placental lactogen, human chorionic gonadotrophin, placental alkaline phosphatase, albumin and alpha 2-macroglobulin. There were also significant correlations between estradiol and sex-hormone binding globulin as well as transcortin in peripheral maternal plasma.

Adult↗

PubMed1985

The effects of postnatal handling on the development of the glucocorticoid receptor systems and stress recovery in the rat.

We have examined the effects of postnatal handling of rat pups from Days 1 to 21 on the development of the intracellular, glucocorticoid receptor in the hippocampus, and pituitary transcortin, and corticoid binding globulin in plasma. All animals were sacrificed 10-14h following adrenalectomy and the in vitro receptor assays were performed using 3H dexamethasone (intracellular receptors) or [3H] corticosterone (transcortin and corticoid binding globulin). Early handling resulted in a 30-40% increase in 3H dexamethasone binding (increase in Bmax with no change in Kd) in the hippocampus. In the pituitary handling was associated with a decrease in transcortin binding. There was no effect on plasma corticoid binding globulin. When tested as adults, nonhandled animals hypersecreted corticosterone following the termination of a stressor. This suggests a more efficient adrenocortical negative-feedback system in the handled animals and these data are consistent with previous work on the relationship between hippocampal glucocorticoid receptors and adrenocortical stress recovery.

Adrenal Cortex↗

PubMedDate not supplied

The presence of cortisol receptors in the human amnion.

Cytosol extracts of human amnion tissue contained high affinity binding of cortisol (Ka=2.48+/-1.06 x 10(9) M(-1); n = 30) and low capacity binding of cortisol (Nmax=279+/-15.5 fmol mg(-1) protein). Kinetic studies of cortisol binding resulted in a similar value of Ka to that obtained by Scatchard analysis. Nuclear extracts of amnion tissue contained high affinity binding of cortisol (Ka=5.8+/-1.91 x 10(7) M[-1]) and low binding capacity (Nmax=91.4+/-21.4 fmol mg(-1) protein). Ka values were an order of magnitude higher in cytosol than in blood serum when amnion and blood were obtained from the same individuals. Differences in competitive ligand binding, especially dexamethasone, were observed between the amnion receptor and transcortin in serum. Gel permeation chromatography gave only one peak at 320 kDa for amnion receptor and only one peak at 48 kDa for transcortin from serum. When amnion tissue was incubated with or without cortisol, cytosol receptor activity was significantly lower in cortisol treated tissue than in control. The nuclear extracted receptor activity was significantly higher in cortisol treated tissue than control. The Ka values from cortisol treated tissue were significantly lower from control. Together the data support the presence of a specific cortisol receptor in the human amnion that is different from transcortin.

Amnion↗

PubMed1986

The effect of manipulating growth in sheep by diet or anabolic agents on plasma cortisol and muscle glucocorticoid receptors.

1. The cortisol status (total plasma cortisol concentration, free cortisol concentration, transcortin capacity) and the characteristics of skeletal muscle binding for cortisol and dexamethasone were examined in female lambs either implanted with Zeranol or trenbolone acetate or whose dietary intake was restricted. 2. The skeletal muscle glucocorticoid receptor had a high affinity for the glucocorticoid triamcinolone (relative binding affinity 0.85) and cortisol (relative binding affinity 0.51) with virtually no affinity for trenbolone. 3. Trenbolone acetate treatment reduced the binding capacity of sheep skeletal muscle for cortisol within 2 d of implantation. The other treatments had little effect except a small reduction in the animals where food intake was restricted. Similarly, binding capacity for dexamethasone was reduced by trenbolone acetate treatment but was not affected by the other treatments. This reduction in trenbolone acetate-treated animals is, at least in part, due to a reduction in glucocorticoid receptors. 4. Transcortin capacity was elevated by Zeranol treatment but reduced with diet restriction or trenbolone treatment. 5. No support for the suggestion of free cortisol concentration being important in the growth-promoting mechanism of trenbolone or Zeranol was obtained. 6. Although insulin concentrations were not significantly altered by treatment (P greater than 0.05), when combining all the animals there was evidence of a negative correlation between total cortisol/insulin value (P less than 0.05) or free cortisol:insulin value and growth rate (P less than 0.001). Free cortisol was negatively correlated to growth rate (P less than 0.05) and transcortin capacity positively correlated (P less than 0.01).

Anabolic Agents↗

PubMed1975

Effects of oral contraceptive therapy on the circadian patterns of cortisol and thyrotropin (TSH).

The daily variation of serum cortisol and thyrotropin (TSH) has been simultaneously recorded every 30-min. in 4 women taking the same oral contraceptive containing oestrogens and progestogens and in 4 control women. The circadian rhythm of cortisol persisted under contraceptive therapy with about a 2.5 fold elevation of the mean level and amplitude of the basal rhythm. Theoretical equilibrium calculations of the circadian variations of the free, transcortin-bound and albumin-bound cortisol fractions showed that these elevations are explained qualitatively and quantitatively by an oestrogen-induced increase of the same order of the transcortin cortisol-binding sites. As a consequence of the already high saturation of transcortin in normal conditions, the magnitude of the variation of free cortisol level resulting from a burst in cortisol secretion varies with the time of day. The role of albumin as a buffer is thereby emphasized. The early morning maximum, characterizing the normal TSH daily pattern, appeared to be considerably enhanced in women under contraceptive therapy. If the circadian variations of TSH are driven by thyrotropin releasing hormone (TRH), these higher morning peaks probably reflect a higher burst of TRH secretion rather than an increased responsiveness of the pituitary to TRH secretion induced by contraceptive therapy. Finally these results do not support the hypothesis of a regulation of TSH circadian variations by an inhibiotry action of cortisol. Contraceptive therapy does not appear to play a role at the level of the central clock or on the resetting mechanism.

Adult↗

PubMed1982

Vasopressin-related peptides increase the hippocampal corticosterone receptor capacity of diabetes insipidus (Brattleboro) rats.

The binding of [3H]corticosterone to receptors in cytosol of several brain regions and of [3H]dexamethasone to receptors in pituitary cytosol was measured after chronic treatment of homozygous diabetes insipidus rats (Ho-Di) with various neuropeptides. All rats were adrenalectomized 24 h before sacrifice for depletion of endogenous adrenal hormones and at that time administration of the peptides was discontinued. At sacrifice the rats were perfused with saline to remove plasma transcortin from the tissues. The apparent maximal binding capacity for corticosterone and dexamethasone was significantly lower in hippocampus and anterior pituitary (36.8% and 39.2%, respectively) of Ho-Di rats than of homozygous nondiabetic rats (Ho-No) of the same strain. In contrast, the neurointermediate pituitary lobe of Ho-Di rats had more than twice as many (211%) binding sites, whereas neither receptor capacity in hypothalamus and septum nor plasma transcortin in these rats were significantly different from those in Ho-No rats. Treatment of Ho-Di rats with arginine-vasopressin, des-glycinamide arginine vasopressin, or 1-desamino-8-D-arginine-vasopressin daily for 1 week resulted in an elevation of receptor capacity in hippocampus and anterior pituitary near the level observed in nondiabetic controls. No effects on the other brain regions, the neurointermediate pituitary lobe, and on plasma transcortin were observed with these peptide treatments. Administration of oxytocin and ACTH-(4-10) did not affect receptor binding. It is concluded that in the Ho-Di Brattleboro rat the glucocorticoid receptor system in the hippocampus and in the anterior pituitary is selectively affected by neuropeptides related to vasopressin.

Animals↗

PubMed1978

Corticosteroidal regulation of the glucocorticoid-binding capacity of rat heart cytoplasmic fraction.

The effects were studied of variations in blood corticosteroid levels on the glucocorticoid-binding capacities of two types of complex-forming substances, whose presence in the myocardium had been established in previous studies. The hormone binding was assessed by the method of adsorption of free forms of steroids on activated dextrancoated charcoal with application of Scatchard's analysis. The binding capacity was tested both in the presence of endogenous steroids and in cytoplasmic fraction made free of the hormones. After adrenalectomy, experimental stress, and administration of exogenous glucocorticoids the concentration of the complex-forming substance I changed in parallel with changing blood transcortin levels. This finding corroborates the concept that the complex-forming substance I is an intercellular (and possibly partially also intracellular) pool of transcortin or a transcortin-like protein; this pool regulates the accessibility of glucocorticoids to the cytoreceptor proper. The intracellular concentration of the complex-forming substance II (performing the function of receptor) changed only little with varying corticosteroid levels, and variations in its binding capacity evidently resulted from shifts in the equilibrium between the "occupied" and "free" findings sites as well as in the distribution of this protein between the cytoplasmic and nuclear fractions.

Adrenalectomy↗

PubMed1981

Plasma protein-binding parameters of prednisolone in immune disease patients receiving long-term prednisone therapy.

Prednisone and prednisolone bind in plasma to albumin and transcortin. In am attempt to determine whether prednisone side effects and/or type of disease correlated with prednisolone plasma protein binding, multiple plasma samples from 17 patients (three asthma, eight SLE, three RA, two PSS, one PAN) receiving long-term prednisone therapy were monitored during an interval between two prednisone doses. Prednisolone plasma protein binding was nonlinear and exhibited large intrapatient and interpatient variability. For the group, mean association constants of the prednisolone-albumin complex and the prednisolone-transcortin complex were 2.3 X 10(3) M-1 and 2.9 X 10(7) M-1, with coefficients of variation of 82% and 127%, respectively. SLE patients tended to have lower mean prednisolone association constants for albumin and transcortin than did other patients. The presence of corticosteroid side effects did not correlate with prednisolone plasma protein-binding parameters. The wide range of prednisolone free fraction noted in plasma from patients who achieved comparable total prednisolone plasma concentrations implies that administration of a uniform prednisone dose will not lead to a predictable clinical response.

Adolescent↗

PubMed1977

[Binding of cortisol, fluocortolone and difluocortolone to human plasma proteins (author's transl)].

The binding properties of [3H]cortisol, [3H]fluocortolone and [3H]difluocortolone by human plasma, human albumin, human- beta- and gamma-globulins have been studied by equilibrium dialysis. Cortisol, in physiological concentrations (0,4 micromol/l), is 98% bound in human plasma at 25 degrees C, fluocortolone 96% and diflucortolone 85%. Uncer physiological conditions cortisol is mainly bound to the corticosteroid binding globulin (transcortin). 2/3 of fluocortolone is bound to transcortin and 1/3 to albumin and globulins, whereas difluocortolone is mainly bound to albumin and to globulins but not to transcortin. The binding affinities of beta- and gamma-globulins are -ery low for the corticoids investigated, but they are higher for fluocortolone and difluocortolone than for cortisol.

Carrier Proteins↗