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At least 415 records · Page 23Linked to original sources
PubMed1983

Corticosteroid receptors in the kidney of chick embryo. I. Nature and properties of corticosterone receptor.

Cytosol from kidney of chick embryo (age 16-18 days) contained a corticosterone-binding site with the features of a putative receptor. This receptor was a thermolabile protein, readily digested by proteolytic enzymes, with a sedimentation coefficient of 7-8 S and with an apparent molecular weight greater than 100,000. Simultaneous studies with transcortin (CBG) revealed several differences between the renal- and serum-binding protein pertaining to the effect of temperature, the sedimentation coefficient, the charcoal "stripping" and, finally, the binding and competition of various steroids for the two proteins. Kinetic analysis showed a rapid association (10 min), which followed second-order reaction kinetics, and a dissociation of pseudo-first-order reaction kinetics with a t1/2 of 168 min at 0 degrees. The analysis of the Scatchard plot showed the presence of a single class of binding sites with an association constant (KA) of 1.3 X 10(8)M-1 and a binding capacity (nmax) of 500-700 fmol/mg protein. We obtained similar results when we used dexamethasone as a ligand. The association (ka) and dissociation (kd) rate constants were respectively 2.9 X 10(6)M-1 sec-1 and 6.86 X 10(-5) sec-1. From their ratio a KA value of 4.2 X 10(10) M-1 was obtained. Studies with various steroids demonstrated that only dexamethasone and, to a lesser degree, progesterone competed for the binding site. These data showed that the kidney of chick embryo possessed one type of receptor for the glucocorticoids, which was similar to the type II described in rat kidney.

Animals↗
PubMed1982

Effect of corticosteroid binding proteins on the steroidogenic activity of bovine adrenocortical cell suspensions.

The possible role of steroid binding proteins in the hormonal secretion process of a steroidogenic tissue was examined using bovine adrenocortical cell suspensions, either under basal conditions or in the presence of half-maximally active concentration (1 x 10(-9) M) of synthetic adrenocorticotropic hormone (ACTH). Three types of plasma cortisol binding proteins were used, namely bovine serum albumine (BSA), purified transcortin (CBG) and purified anticortisol immunoglobulins (IgG). When added to the incubation medium, CBG (at 1 x 10(-10) to 2 x 10(-9) M cortisol binding sites) and anticortisol IgG (at 4.8 x 10(-10) to 3 x 10(-9) M cortisol binding sites) did not influence either the basal nor the ACTH-stimulated net cortisol production of the cell preparations. Whereas crystallized and delipidated BSA showed also no effect, crude commercial BSA preparation (Cohn fraction V) exhibited an ACTH-like cofactor effect which resulted in a marked increase in the net cortisol production by stimulated cells. These observations might be explained by the presence in crude BSA of lipoprotein-cholesterol complexes, possibly acting as an extracellular source of cholesterol available for corticosteroidogenesis. It may be concluded that specific high affinity cortisol binding systems present outside adrenocortical steroidogenic cells do not influence their secretory activity under short term in vitro condition. In addition, it can be stressed that use of ill defined protein preparations (e.g. crude BSA) may lead to artifactual observations in the study of the differentiated functions of isolated steroidogenic cells.

Adrenal Cortex↗
PubMed1983

Binding of prednisolone to alpha 1-acid glycoprotein.

The binding of prednisolone to alpha 1-acid glycoprotein (AGP) was determined in vitro by equilibrium dialysis. The effects of temperature, protein concentration, and drug concentration were evaluated. The binding ratio (bound/free) correlated well with protein concentration (r = 0.958) and percent bound ranged from 2 to 12% over high to low prednisolone concentrations at physiologic AGP concentrations (100 mg/dl). Temperature changes did not perturb binding. The non-linear regression estimate of the binding constant (nk) was 4.4 x 10(3) M-1 indicative of both low affinity and low capacity of AGP for prednisolone. Overall, contribution of AGP to the total plasma binding of prednisolone is less than 3% when considered in the competitive protein binding system with transcortin and albumin. Disease induced alterations of AGP concentrations are relatively unimportant regarding plasma protein binding of prednisolone.

Humans↗
PubMed1987

Equivalent affinity of aldosterone and corticosterone for type I receptors in kidney and hippocampus: direct binding studies.

In studies from several laboratories evidence has been adduced that renal Type I (mineralocorticoid) receptors and hippocampal "corticosterone-preferring" high affinity glucocorticoid receptors have similar high affinity for both aldosterone and corticosterone. In all these studies the evidence for renal mineralocorticoid receptors is indirect, inasmuch as the high concentrations of transcortin (CBG) in renal cytosol make studies with [3H]corticosterone as a probe difficult to interpret, given its high affinity for CBG. We here report direct binding studies, with [3H]aldosterone and [3H]corticosterone as probes, on hippocampal and renal cytosols from adrenalectomized rats, in which tracer was excluded from Type II dexamethasone binding glucocorticoid receptors with excess RU26988, and from CBG by excess cortisol 17 beta acid. In addition, we have compared the binding of [3H]aldosterone and [3H]corticosterone in renal cytosols from 10-day old rats, in which CBG levels in plasma and kidney are extremely low. Under conditions where neither tracer binds to type II sites or CBG, they label an equal number of sites (kidney 30-50 fmol/mg protein, hippocampus approximately 200 fmol/mg protein) with equal, high affinity (Kd 4 degrees C 0.3-0.5 nM). Thus direct tracer binding studies support the identity of renal Type I mineralocorticoid receptors and hippocampal Type I (high affinity, corticosterone preferring) glucocorticoid receptors.

Aldosterone↗
PubMed1980

Comparison of plasma corticosterone- and progesterone-binding activity in rat and human.

Corticosterone-and progesterone-binding activity were measured by saturation analysis, with dextran-charcoal separation, in plasma obtained from male and female rats, and a normal male and female human. In plasma from normal male and female rats, progesterone was much less effective than corticosterone in displacing 3H-corticosterone from plasma protein binding sites although the parallelism of the displacement curves indicated competition for the same binding sites. In plasma from the normal male human, corticosterone and progesterone were equally effective in displacing 3H-corticosterone. However, 3H-progesterone showed no apparent binding to either rat or human plasma proteins, suggesting that dextran-charcoal effectively removed progesterone from transcortin binding sites at 4 degrees C. This observation was confirmed by multiple equilibrium dialysis. In dialysis, 3H-corticosterone and 3H-progesterone were bound equally by human plasma, but rat plasma bound 3H-corticosterone to a much greater extent than it did 3H-progesterone. These data indicate that, in contrast to human plasma, rat plasma has much greater affinity for corticosterone than for progesterone.

Adult↗
PubMed1994

Corticosteroid-binding globulin mRNA levels in human uterine endometrium.

Corticosteroid-binding globulin (CBG or transcortin) is a specific plasma glycoprotein, which binds steroid hormones (cortisol, corticosterone, and progesterone), and plays a role in transporting these steroids, altering their concentrations in blood, and influencing their biological actions. CBG has been previously shown to be synthesized in the liver, but recently it has been reported that immunoreactive CBG is localized in target tissues. In the present work, CBG mRNA was detected in normal human endometrial tissues by Northern blot analysis and reverse transcription-polymerase chain reaction. Its level was higher (P < 0.05) in the secretory phase than in the proliferative phase. In the secretory phase, the endometrial CBG mRNA level was negatively correlated with the serum progesterone level (P < 0.01). While there was no positive correlation between the levels of endometrial CBG mRNA and serum estradiol (E2), there was a positive correlation between the endometrial CBG mRNA level and the serum E2/progesterone ratio (P < 0.05). These findings suggest that CBG is synthesized in the uterine endometrium, predominantly in the secretory phase, and that the serum E2/progesterone ratio exerts an influence on the synthesis of intracellular CBG.

Adult↗
PubMed1986

The multifactorial nature of osteoporosis: the potential of corticosteroid-binding globulin as a unifying regulator.

Accelerated bone loss often accompanies the menopause, and may also affect a significant proportion of ageing women. This osteoporosis can also be an accompaniment of several other pathological manifestations. It is difficult to imagine that each process alters bone resorption and renewal by a separate mechanism; in all probability a common mechanism may operate in some of the instances where osteoporosis is observed. It is proposed that chronic alterations in the levels of circulating physiologically-active cortisol could account for some of the osteoporoses. These alterations need not necessarily affect total plasma cortisol values, but rather affect the relationship of cortisol to its plasma carrier protein, transcortin, since changes in this relationship are a common occurrence in many of the conditions associated with osteoporosis.

Calcitonin↗
PubMed1991

Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate.

An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.

Androstadienes↗
PubMed1992

Glucocorticoid-recognizing and -effector sites in rat liver plasma membrane. Kinetics of corticosterone uptake by isolated membrane vesicles--I. Binding and transport.

To gain insight into the mechanisms governing cellular uptake of glucocorticoids, we studied the binding and membrane transport of corticosterone (B) on a highly purified plasma membrane fraction from rat liver that was homogenized using a gentle, isotonic procedure. The fraction was mostly in the form of right-side out and osmotically active vesicles that were free of intracellular glucocorticoid receptors (GCR), transcortin (CBG) and ATP. Our uptake and binding studies carried out at 22 degrees C with [3H]B in physiological concentrations resulted in the following findings: (1) unlabeled B competed with [3H]B for uptake by the membrane vesicles; half-maximal competition of specific uptake was achieved with a 10- to 11-fold molar excess of unlabeled B. (2) [3H]B uptake was a saturable process of unusual kinetics (multiple sigmoidity); modified Scatchard plots revealed three significantly different apparent Kd-values of 1.3, 4.7 and 17.3 nM, corresponding to free B in the blood of non-stressed rats (4-16 nM). (3) Osmotic shrinkage of the vesicles led to a linear decrease in specific uptake, while non-specific uptake was independent of vesicle volume. Passive diffusion of [3H]B took place in leaky, but not in intact, vesicles. Reversible binding to, and mediated transport through, the membrane were interdependent parts of a strongly linked process. B was accumulated inside the vesicle up a concentration gradient by an active transport that followed first-order kinetics (Kt:3.9 nM); for its statistically reliable mathematical formulation and kinetic analysis, a replot was developed that revealed that relative accumulation increased with decreasing external hormone concentration. (4) Comparative binding studies disclosed that the apparent Kd-values (86.5 +/- 7.3 and 77.0 +/- 14.3 nM, respectively) of the [3H]B interactions with CBG and GCR did not differ (P greater than 0.3). These findings permit the conclusion that a plasma membrane-inserted carrier for B, effectively operating at physiological concentrations in the blood, is involved in a functional and regulatory manner in the biological action of glucocorticoids.

Animals↗
PubMed1992

Glucocorticoid-recognizing and -effector sites in rat liver plasma membrane. Kinetics of corticosterone uptake by isolated membrane vesicles--II. Comparative influx and efflux.

To elucidate the initial step in the interaction between glucocorticoids (GC) and the hepatocyte, we examined at 22 degrees C further kinetic properties of active corticosterone (B) transport mediated by a putative, plasma membrane-inserted carrier for GC (GCC) as previously reported [Alléra and Wildt, J. Steroid Biochem. Molec. Biol. 42 (1992) 737-756]. We used a purified, well-characterized, osmotically active vesicle fraction of plasma membrane (PM), free of ATP, isolated from rat liver and a method developed by us to describe transport processes mathematically: (1) uptake (U) of 7 nM B into the vesicles (influx, I) occurred very rapidly whereby T1/2 = 8.3 s, the time (S) required for half maximum transport; the influx velocity (dU/dS = V) decreased degressively with time following second-order kinetics characterized by an initial transport V (VT0) of 177.7 fmol/mg membrane protein/s. (2) VToI of B-influx rose with temperature biphasically (P less than 0.025): activation energy above and below 15 degrees C (at PM phase transition) amounted to 9.5 and 26.5 kJ/mol. Neither at 45 nor at 60 degrees C did transport take place, revealing the high thermolability of GCC. (3) Efflux (E) of 6.5 nM B, i.e. transport out of the vesicles preincubated with the steroid, showed that influx had resulted in a 19.6-fold intravesicular hormone accumulation, indicating active ("uphill") transport. (4) The efflux velocity (dE/dS = V) exhibited almost the same kinetic quality as that of influx: it decreased following mainly second-order kinetics whereby T1/2 = 8.0 s. However, its whole time-course was much slower and the VT0 of efflux (VToE) was 6.3 lower than VToI. (5) Using physics and thermodynamics, we deduced that the affinity (AF) between B and GCC is proportional to the square of VT0. (6) Thus, because AF approximately (1/6.3)2, AF of the B-GCC interaction after completion of influx was calculated to be 40 times lower (Kd = 708 nM; delta G degrees = -34.9 kJ/mol) than at outset of influx, whereby delta G degrees = -44.0 kJ/mol. Concluding from these and previous findings, we present a new hypothesis on B transport into the hepatocyte: There is no difference (P greater than 0.3) in free enthalpy between transcortin (CBG) and the intracellular GC receptor interacting with B (delta G degrees = -40.1 and -40.4 kJ/mol). The GCC, however, is characterized by its ability to switch from a high- to lower-affinity when interacting with B (and vice versa due to metabolic energy input).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

The raising and characterization of cortisol-binding antiserum.

Synthesis of a cortisol-albumin compound and the raising of antibodies against cortisol in rabbits are described in detail. The steroid-protein complex is characterized by a number of reactions regarding the amount of cortisol coupled and the ability of the coupled steroid to react as such. The specificity of the harvested antiserum and transcortin towards the coupling of several related steroids are compared; the rabbit antiserum appears to be the more selective binding agent.

Animals↗
PubMed1998

Hypothalamic-pituitary-adrenal axis activity in the inbred Brown Norway and Fischer 344 rat strains.

We have examined the basal and the stress-induced secretion of corticosterone in relation to the expression of adrenal steroid receptors in the pituitary, hypothalamus and hippocampus of the inbred Brown Norway and Fischer 344 rat strains. Our data indicated that plasma transcortin and integrated plasma corticosterone levels were significantly higher in Fischer 344 compared to Brown Norway rats. Fischer 344 hypersecrete corticosterone during the dark phase of the diurnal cycle and during the phase of recovery following a 20 min period of restraint stress compared to Brown Norway rats. This hypersecretion of corticosterone was negatively correlated with the size of the adrenal gland but might be related to the higher density of mineralocorticoid receptors in the hippocampus of Fischer 344 rats.

Adrenal Glands↗
PubMed1975

A competitive protein binding radioassay for deoxycorticosterone in human plasma.

A simple, sensitive and reliable competitive protein binding radioassay using dog transcortin has been developed for the measurement of 11-deoxycorticosterone (DOC) in human plasma. A 1% plasma solution from dexamethasone treated male dogs served as the source of the binding protein. Sephadex LH-20 column chromatography was used for the separation of the steroid prior to assay. The method is sensitive enough to detect 50 pg of DOC. The intra- and interassay co-efficients of variation were 11.5% and 11.3% respectively. Water blanks and plasma blanks from adrenalectomized rats and humans gave negligible readings for DOC. Support for the identity of the steroid being assayed as DOC was obtained by subjecting a plasma pool to multiple radioassays using 4 different binding proteins including 2 anti-DOC antibodies. The values obtained in all 4 systems were in good agreement confirming the fact that DOC was the steroid being measured. Morning plasma DOC levels measured in 29 healthy subjects averaged 8.0 plus or minus 1.2 (S.E.) ng% in 14 males, and 8.7 plus or minus 0.9 (S.E.) ng% in 15 females (p greater than 0.3).

Animals↗
PubMed1978

Kinetic and equilibrium studies on steroid interaction with human corticosteroid-binding globulin.

Kinetic and equilibrium studies on the interaction of steroids with human corticosteroid-binding globulin (CBG, transcortin) were performed with pH, temperature, and steroid structure as variables. Dissociation rate constants were determined fluorometrically; the values for cortisol, corticosterone, deoxycorticosterone, and progesterone are 0.031, 0.047, 0.10, and 0.16 s-1, respectively, at 20 degrees C, pH 7.4. The pH dependence of the dissociation rate constant for the corticosterone complex below pH 10.5 at 20 degrees C is given by koff = 0.043 (1 + [H+]/10(-6.50)) s-1; above pH 11, koff = 0.030 (1 + 10(-12.15/[H+] s-1. A temperature-dependence study of koff for the cortisol and progesterone complexes gave values of 0.0028 s-1 and 0.012 s-1 at 4 degrees C, respectively, and 0.88 s-1 and 4.5 s-1 at 37 degrees C, with progesterone dissociating about four to five times faster over the entire temperature range. The affinity constants, determined by equilibrium dialysis, for the binding of cortisol, corticosterone, and progesterone at 4 degrees C were 7.9, 7.2, and 7.0 X 10(8) M-1; values of 0.40 and 0.26 X 10(8) M-1 were determined at 37 degrees C for cortisol and progesterone. The close similarity of the affinity constants of the three steroids combined with differing dissociation rates implies that the association rate changes with steroid structure, in contrast to our earlier findings with progesterone-binding globulin.

Adrenal Cortex Hormones↗
PubMed1979

Effects of phorbol 12-myristate 13-acetate and cortisol interaction on steroid-binding capacity in the rat.

The specificity of the cortisol-receptor protein is examined in plasma and liver cytosol of rats. Phorbol 12-myristate 13-acetate does not inhibit the binding of cortisol to transcortin, nor does it affect the binding capacity of dexamethasone to the intracellular glucocorticoid receptor, but, by interacting with the cortisol molecule, it interferes with hormone-mediated processes in the cell.

Animals↗
PubMed1997

Dynamic variations in plasma corticosteroid-binding globulin and basal HPA activity following acute stress in adult rats.

We report on dynamic changes in plasma corticosteroid-binding globulin (CBG) binding and basal hypothalamic-pituitary-adrenal (HPA) activity following acute stress in adult rats. Plasma CBG binding was significantly reduced at 24 and 48 h following a single 60 min period of restraint. Basal levels of plasma ACTH and total corticosterone (B) during the light phase of the cycle were elevated at 24 h following restraint. These effects occurred only when animals were stressed in the light phase of the cycle; animals exposed to restraint stress during the dark phase of the cycle showed no change in plasma CBG binding or in basal HPA activity. Pituitary intracellular transcortin, which is derived from circulating CBG, was also decreased by restraint stress. The decrease in CBG binding was also associated with a significant increase in resting-state free B levels. Together, these effects produced a substantially (i.e. approximately 10-fold) increased 'basal' glucocorticoid signal 24 h following acute stress. These data suggest that the increase in the circulating glucocorticoid signal associated with acute stress endures well beyond the period of increased total B levels.

Adrenal Glands↗
PubMed2000

Is the mineralocorticoid receptor in Brown Norway rats constitutively active?

In a previous study using corticosterone treatment of adrenalectomized rats, we hypothesized that mineralocorticoid receptor (MR)-related mechanisms are constitutively active and that glucocorticoid receptor (GR)-mediated mechanisms are more efficient in Brown Norway rats compared to Fischer 344 (F344) rats. In order to discriminate the mineralocorticoid from the glucocorticoid actions exerted by corticosterone, F344 and Brown Norway adrenalectomized rats were treated with increasing doses (1, 5 and 25 microg/ml of drinking water) of deoxycorticosterone (DOC, MR-specific ligand) or RU 28362 (GR-specific ligand). These rats were compared with long-term adrenalectomized (ADX) untreated rats and sham-ADX rats. This study confirms our previous results, notably the lack of effect of ADX on body weight and fluid intake in Brown Norway rats. Moreover, DOC treatment had no effect in Brown Norway rats whereas the higher dose restored fluid intake of the F344 ADX group to sham values. These results support the hypothesis of a constitutive activation of the MR and therefore the insensitivity of this receptor to its ligand in Brown Norway rats. Alternatively, RU 28362 treatment induced greater weight loss, decrease in food intake, anxiolysis, thymus involution, and decrease in plasma transcortin concentration and pituitary corticosteroid receptor densities in Brown Norway rats than in F344 rats, which is consistent with greater efficiency of GR mechanisms in Brown Norway rats than in F344 rats. Therefore, these strains are of great utility to disentangle MR and GR effects on complex phenotypes.

Adrenalectomy↗
PubMed1991

Consideration on some hormone binding proteins patterns during pregnancy.

Serum concentrations of sex hormone binding globulin, transcortin, thyroxine binding globulin, transthyretin together with retinol binding protein, ceruloplasmin, transferrin and albumin were measured sequentially in pregnant women in order to derive more definite suppositions relating to the prime function of hormone binding proteins. Thus, the fact that except for transthyretin all other specific hormone binding proteins exhibited appreciable but significantly variable increases would suggest: a) the apparent existence of more complex mechanisms regulating protein metabolism during pregnancy than hitherto postulated (i.e. the general notion of an integrated estrogen influence); b) a major and distinctive role for each of the hormone binding proteins is plausible since alterations in hormonal requirements by the fetus as pregnancy progresses can not be provided by the almost constant transplacental transfer rate of the "free" hormone moiety.

Adult↗