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PubMed2003

Plasma levels of cortisol and corticosteroid-binding globulin (CBG) and hepatic CBG mRNA expression in pre- and postnatal pigs.

The relationships among hepatic corticosteroid-binding globulin (CBG) mRNA expression and plasma concentrations of cortisol and CBG was evaluated in fetal pigs (n=7-14 per age) on days 50, 70, 80, 90, and 104 of gestation and postnatal pigs (n=8 per age) on days 1, 3, 10, 20, 30, and 40 following birth. In fetal pigs, hepatic CBG mRNA expression was highest (P<0.01) on day 50 as compared to days 90 and 104, exhibiting an overall negative relationship (r=-0.63; P<0.01) with estimated gestation age. Plasma porcine CBG (pCBG) concentration was correlated (r=0.34; P<0.05) with hepatic CBG mRNA level. Plasma cortisol concentrations were not different over this same period. In postnatal pigs, hepatic CBG mRNA expression increased (P<0.01) from days 3 to 40. The pCBG concentration increased (P<0.01) from days 1 (6.1+/-3.4 microg/ml) to 10 (15.1+/-3.7 microg/ml), while plasma cortisol concentration remained constant. An understanding of the relation between hepatic CBG mRNA and circulating pCBG concentrations may provide insight into the mechanisms determining the bioavailability of cortisol necessary in prenatal development and the conservation of cortisol during postnatal development in the pig.

Aging↗
PubMed2002

Access of reproductive steroids to target tissues.

The access of reproductive steroids to their target cells varies considerably between tissues, and is influenced to a great extent by their interactions with plasma steroid-binding proteins, and with SHBG and CBG in particular. An increased awareness of how SHBG and CBG function within the blood circulation, and within extravascular compartments of steroid-responsive target tissues, needs to be incorporated into the design and evaluation of therapies involving the administration of both natural and synthetic steroids, which influence female reproduction and healthy aging.

Female↗
PubMed1999

The stressful condition as a nutritionally dependent adaptive dichotomy.

The injured body manifests a cascade of cytokine-induced metabolic events aimed at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones work in concert with cytokines to generate overall insulin and insulin-like growth factor 1 (IGF-1), postreceptor resistance and energy requirements grounded on lipid dependency. Salient features are self-sustained hypercortisolemia persisting as long as cytokines are oversecreted and down-regulation of the hypothalamo-pituitary-thyroid axis stabilized at low basal levels. Inhibition of thyroxine 5'-deiodinating activity (5'-DA) accounts for the depressed T3 values associated with the sparing of both N and energy-consuming processes. Both the liver and damaged territories adapt to stressful signals along up-regulated pathways disconnected from the central and peripheral control systems. Cytokines stimulate liver 5'-DA and suppress the synthesis of transthyretin (TTR), causing the drop of retinol-binding protein (RBP) and the leakage of increased amounts of T4 and retinol in free form. TTR and RBP thus work as prohormonal reservoirs of precursor molecules which need to be converted into bioactive derivatives (T3 and retinoic acids) to reach transcriptional efficiency. The converting steps (5'-DA and cellular retinol-binding protein-I) are activated by T4 and retinol, themselves operating as limiting factors of positive feedback loops. Healthy adults with normal macrophage functioning and liver parenchymal integrity, who submitted to a stress of medium severity, are characterized by TTR-RBP plasma levels reduced by half and an estimated ten-fold increase in free ligand disposal to target cells during the days ensuing injury. This transient hyperthyroid and hyperretinoid climate creates a second defense line strengthening and fine-tuning the effects primarily initiated by cytokines. The suicidal behavior of thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG), and IGFBP-3 allows the occurrence of peak endocrine and mitogenic influences at the site of inflammation. The production rate of TTR by the liver is the main determinant of both the hepatic release and blood transport of holoRBP, which explains why poor nutritional status concomitantly impairs thyroid- and retinoid-dependent acute-phase responses, hindering the stressed body to appropriately face the survival crisis. The prognostic significance of low TT4 blood levels may be assigned to the exhaustion of extrathyroidal hormonal pools normally stored in liver and plasma but markedly shrunken in protein-depleted states. These data offer new insights into the mechanisms whereby preexisting malnutrition and stressful complications are interrelated, emphasizing the pivotal role played by TTR in that context.

Adaptation, Physiological↗
PubMed1993

Immunohistochemical localisation of the 90, 70 and 25 kDa heat shock proteins in control and caffeine treated rat embryos.

Human and animal experimental data demonstrate that in utero exposure to caffeine results in intrauterine growth retardation and long-term behavioural and reproductive effects. We have suggested that the disruption of normal transcription and translation associated with the initiation of the heat shock response may be a possible mechanism of action of caffeine. This hypothesis was investigated using immunohistochemistry to determine whether an acute (3 h) dose of 30 mg/kg caffeine alters the distribution of hsp 90, 70 and 25 in 10.5-12.5 g.d. rat embryos. In the control embryos hsps 90 and 70 were distributed throughout the embryo with no areas of specific accumulation. Hsp 25 was localised to the developing myocardium of 10.5, 11.5 and 12.5 g.d. embryos and the myotome of 11.5 and 12.5 g.d. embryos. The appearance of hsp 25 was correlated with the onset of muscle fibre differentiation and it is suggested that hsp 25 is associated with cytoskeletal proteins. Following dosing with caffeine no change in the distribution of staining for hsp 90, 70 and 25 was found. These results strongly suggest that caffeine's mechanism of action does not involve initiation of the heat shock response.

Animals↗
PubMed1997

Glucocorticoids induce corticosteroid-binding globulin biosynthesis by immature mouse liver and kidney.

Marked changes in mouse corticosteroid-binding globulin (CBG) gene expression in the liver and kidney occur postnatally. To study the influence of glucocorticoids on the initiation of mouse CBG biosynthesis in these tissues during the first two weeks after birth, we administered dexamethasone (0.5 microgram/g body wt/day) to 4- and 11-day-old pups for three days. This resulted in higher serum CBG and hepatic CBG mRNA levels in animals, irrespective of their ages. Higher relative amounts of CBG mRNA in the kidneys of 14-day-old pups after three days of dexamethasone treatment co-incided with higher amounts of intact and proteolytically cleaved CGB in their urine, and both are indicative of increased CGB production by the developing renal tubules. When an additional group of 11-day-old pups (n = 4) was treated with 0.25 microgram dexamethasone/g body weight per day for five days, this also resulted in significantly higher levels of serum CBG (P < 0.01), hepatic CBG mRNA (P < 0.01) and renal CBG mRNA (P < 0.05), compared to littermates treated with the oil vehicle alone. In contrast, serum CBG levels progressively decreased in adult female mice during five days of treatment with 0.5 microgram dexamethasone/g body weight per day. Taken together, these data indicate that glucocorticoids induce murine CBG gene expression in the immature liver and kidney, and support the concept that the effects of glucocorticoids on CBG gene expression are developmentally stage-specific.

Age Factors↗
PubMed1997

Isotope effect in the binding of tritium and 14C-labelled cortisol to corticosteroid-binding-globulin in serum.

We have determined the free cortisol concentration in serum using either the Amicon MPS-1 ultrafiltration-centrifugation method (I) or equilibrium dialysis (II). If procedure I was used we found that [1,2,6,7-3H]-, and [4-14C]cortisol had a lower affinity than unlabelled cortisol for corticosteroid binding globulin (CBG). The binding affinity (Ka) to three separate CBG-containing samples was 8-18 times lower for [1,2,6,7-3H]cortisol and 30-90 times lower for [4-14C]cortisol, when compared with that of unlabelled cortisol. This difference in affinity to CBG was not observed if method II was used for the free cortisol determinations. The observed isotope effect in method I is not caused by unspecific binding to material such as the Amicon MPS-1 chamber or to impurities in the tracer. We suggest that the centrifugation step during ultrafiltration changed the conformation of CBG, thereby reducing its affinity for labelled cortisol. It is concluded that incorrect results will be obtained if radiolabelled is cortisol used for determining the free cortisol content of plasma with the Amicon MPS-1 device.

Artifacts↗
PubMed1997

High-affinity binding of corticosterone to mammalian neuronal membranes: possible role of corticosteroid binding globulin.

The signal transduction mechanisms mediating rapid steroid actions are poorly understood. To characterize corticosteroid interaction with neuronal membranes in a species with rapid behavioral responses to corticosterone, we examined [3H]corticosterone binding to membranes prepared from prairie vole brains. At 22 degrees C, the rates of association and dissociation of [3H]corticosterone with well-washed synaptosomal membranes were very rapid. Specific binding was characterized by high affinity (Kd = 6.01 nM) and low density (Bmax = 63.1 fmol/mg protein). The binding sites were highly specific for naturally occurring glucocorticoids and the density of binding sites appeared to vary by neuroanatomical region. Unlike most G-protein-coupled receptors, the high-affinity binding of [3H]corticosterone to vole brain membranes was unaffected by the addition of Mg2+ or guanyl nucleotides. Surprisingly, saline perfusion of vole brains before tissue homogenization greatly reduced high-affinity binding. In addition, the affinity and specificity of corticosteroid binding sites were similar in vole neuronal membranes and vole plasma. These data suggest that corticosteroid binding globulins may facilitate [3H]corticosterone binding to neuronal membranes. However, the addition of blood to perfused brains before homogenization did not restore high-affinity binding, so the role of plasma binding globulins is unclear. Whether these binding phenomena represent a technical artifact or a regulatory mechanism for corticosteroid action has yet to be determined.

Animals↗
PubMed1998

Influence of calf serum on glucocorticoid-responses of certain progesterone derivatives.

UNLABELLED: The following in vitro glucocorticoid (GC) parameters of progesterone (P), 1-ene progesterone (deltaP), 11beta-hydroxyprogesterone (HOP), 11beta-1-ene progesterone (deltaHOP) and dexamethasone (Dexa) were assayed in the presence or absence of bovine calf serum (BCS): binding to thymus cytosol, dissociation of the glucocorticoid receptor (GR)-heat shock protein 90 (hsp90) complex (diss.), tyrosine aminotransferase (TAT) induction in hepatocytes and the inhibition of 3H-uridine and 35S-methionine uptake by thymocytes. Without BCS, steroids were in most cases active in this general order: Dex > deltaHOP > HOP > deltaP > P. BCS abolished all activities in P and deltaP, but left them unaltered in all other steroids, except diss. in HOP, which diminished intermediately. Binding of P, deltaP, HOP and deltaHOP to GR and CBG paralleled their in vivo activating effects on glycogen deposition. CONCLUSIONS: in this steroid series, BCS, but not CBG, inhibits GC responses of P and deltaP. 11-Beta hydroxylation frees those molecules from the inhibitory effects of BCS.

Adrenalectomy↗
PubMed1998

Effect of oleoyl-estrone administration on corticosterone binding to tissues of lean and obese Zucker rats.

A group of female Zucker lean and obese rats was treated with 3.5 micromol/day kg of oleoyl-estrone in liposomes (OE) injected i.v. continuously for 14 days with inserted osmotic minipumps. Samples of liver were extracted on days 0, 3, 6, 10 and 14 and the expression of corticosterone-binding globulin (CBG) was determined by Northern blot. On the same dates, the total binding capacity of plasma, liver, periovaric white adipose tissue (WAT) and subcutaneous WAT was also determined using tritium-labelled corticosterone. Treatment with OE resulted in diminished CBG gene expression in the liver, this being more marked in the obese rats. Basal (time 0) corticosterone binding was higher in the plasma, liver and WAT of lean rats. Treatment with OE resulted in a gradual and general loss of binding capacity in the plasma and all tissues studied, for lean and obese rats alike. Since CBG decreases may result in enhanced glucocorticoid availability (and effects), the global decrease in corticosterone binding observed can be interpreted as a counteractive response to the energy imbalance elicited by OE.

Adipose Tissue↗
PubMed2003

Study of the binding affinity for corticosteroid-binding globulin (CBG) using the electron topological method (ETM) as three-dimensional quantitative structure-activity relationship (3D QSAR).

The Electron Topological Method, called ETM, is a descriptor for predicting the biological activities of molecules based on three-dimensional quantitative structure-activity relations (3D QSAR). ETM uses a modified electron topological state index to substitute for electronic properties and a topological distance for the relative distance in the molecule. It is shown that the molecular fragments responsible for this activity possess fixed electronic and geometric characteristics associated with a distinct arrangement and the steric accessibility of an oxygen atom and a group of carbon atoms. After that, it is essential to employ a linear regression analysis technique to derive a 3D QSAR model relating the biological activities to the ETM. The ETM is used to study the 3D QSAR of the corticosteroid-binding globulin (CBG) binding affinity to 31 steroids, and resulting models have a comparable to current 3D methods such as CoMFA. Though the ETM is a descriptor based on 3D topological information obtained by quantum chemical derived descriptors, give the best answer for both the similarity analysis and the statistical fitting.

Electrons↗
PubMedDate not supplied

Biologic effects of delta-8-estrone sulfate in postmenopausal women.

OBJECTIVE: To determine in postmenopausal women the biological effects of delta-8-estrone sulfate, a novel estrogen component of Premarin (Wyeth-Ayerst, Philadelphia, PA). METHODS: An open-label, nonrandomized study of six healthy postmenopausal women was conducted. Each subject took 0.125 mg of delta-8-estrone sulfate daily for 8 weeks. Blood samples were collected at day 0 (baseline) and once a week for 8 weeks. Urine was collected on day 0 and at weeks 2, 3, 5, 6, 7, and 8. Serum gonadotropins (follicle-stimulating hormone/luteinizing hormone), plasma binding proteins (corticosteroid-binding globulin/sex hormone-binding globulin), a marker for bone turnover (urinary n-telopeptide), and markers for cardiovascular effects (cholesterol, low-density lipoprotein, high-density lipoprotein(c), low-density lipoprotein oxidation, and rate of diene formation) were measured. RESULTS: Follicle-stimulating hormone levels decreased from 84.0 +/- 8.5 to 67.0 +/- 8.5 mlU/mL (P = .02), whereas luteinizing hormone levels did not change. Corticosteroid-binding globulin levels increased from 3.30 +/- 0.16 to 4.10 +/- 0.16 mg/dL (P = .02), and no change in sex hormone-binding globulin was noted. The n-telopeptide levels decreased an average of 31% from 40.7 +/- 4.9 to 28 +/- 7.0 nmol/L bone collagen equivalents/mmol/L creatinine (P = .03). Plasma diene concentration and diene production rate decreased by 34% and 40%, respectively; these changes were not significantly different from baseline values. In contrast, a significant (P = .03) 68% increase in the lag time for low-density lipoprotein(c) oxidation (38.5 +/- 5.5 minutes versus 64.8 +/- 8.5 minutes) was observed. No significant change occurred in total cholesterol, high-density lipoprotein(c), and low-density lipoprotein(c). CONCLUSION: Small doses (0.125 mg) of delta-8-estrone sulfate have profound estrogenic effects in postmenopausal women. The changes observed in n-telopeptide levels and the lag-time delay in oxidation of low-density lipoprotein(c) indicate that this estrogen contributes toward the overall beneficial effects on bone and cardiovascular system associated with Premarin therapy.

Cholesterol↗
PubMed2002

Beware of q2!

Validation is a crucial aspect of any quantitative structure-activity relationship (QSAR) modeling. This paper examines one of the most popular validation criteria, leave-one-out cross-validated R2 (LOO q2). Often, a high value of this statistical characteristic (q2 > 0.5) is considered as a proof of the high predictive ability of the model. In this paper, we show that this assumption is generally incorrect. In the case of 3D QSAR, the lack of the correlation between the high LOO q2 and the high predictive ability of a QSAR model has been established earlier [Pharm. Acta Helv. 70 (1995) 149; J. Chemomet. 10(1996)95; J. Med. Chem. 41 (1998) 2553]. In this paper, we use two-dimensional (2D) molecular descriptors and k nearest neighbors (kNN) QSAR method for the analysis of several datasets. No correlation between the values of q2 for the training set and predictive ability for the test set was found for any of the datasets. Thus, the high value of LOO q2 appears to be the necessary but not the sufficient condition for the model to have a high predictive power. We argue that this is the general property of QSAR models developed using LOO cross-validation. We emphasize that the external validation is the only way to establish a reliable QSAR model. We formulate a set of criteria for evaluation of predictive ability of QSAR models.

Data Interpretation, Statistical↗
PubMed2002

Three-dimensional molecular descriptors and a novel QSAR method.

A novel set of molecular descriptors suitable for use in quantitative structure-activity relationships and related methods is described. These descriptors are a smooth and interpretable representation of atomic physicochemical property values and intramolecular atom pair distances. Distance atomic physicochemical parameter energy relationships (DAPPER), a novel structure-activity relationship (QSAR) method using these descriptors, is validated on standard datasets.

Chemical Phenomena↗
PubMed1994

Glycosylation of human corticosteroid-binding globulin. Differential processing and significance of carbohydrate chains at individual sites.

Human corticosteroid-binding globulin (CBG) comprises 383 amino acids and six consensus sites for attachment of N-acetyllactosamine-type oligosaccharides. To study the extent of addition and processing of individual carbohydrate chains, we expressed CBG mutants, each containing only one of the six possible glycosylation sites, in Chinese hamster ovary cells and examined their electrophoretic, immunochemical, and lectin-binding properties. This indicated that Asn9, Asn308, and Asn347 are partially glycosylated and that oligosaccharides attached to Asn9, Asn238, Asn308, and Asn347 are predominantly biantennary, while more branched (most likely, triantennary) oligosaccharides are preferentially linked to Asn74 and Asn154. Only one of the biantennary chains (attached to Asn9) contains significant amounts of fucose. These data indicate that oligosaccharide processing is site-specific, and analyses of three other mutants, in which an additional glycosylation site was preserved, demonstrated that the processing of individual oligosaccharides occurs independently. Thus, the glycosylation of recombinant CBG appears to resemble that of natural human CBG. As we have previously found, glycosylation at Asn238 is essential for the production of CBG with steroid-binding activity, but when the mutant containing only one oligosaccharide at this position was enzymatically deglycosylated, its steroid-binding activity was unaltered. This suggests that interaction between this carbohydrate chain and the polypeptide is necessary for the folding and creation of the steroid-binding site only during CBG biosynthesis.

Amino Acid Sequence↗
PubMed1994

Identification of Trp-371 as the main site of specific photoaffinity labeling of corticosteroid binding globulin using delta 6 derivatives of cortisol, corticosterone, and progesterone as unsubstituted photoreagents.

Immunopurified human corticosteroid binding globulin (CBG) was photolabeled with delta 6-[3H]cortisol, delta 6-[4-14C]cortisol, delta 6-[3H]corticosterone, and delta 6-[3H]progesterone. The maximal levels of specific incorporation, as estimated with tritiated photoreagents, were 0.21, 0.14, and 0.08 mol of label/mol of CBG, respectively. Tryptic cleavage of photolabeled CBG gave in all cases a major radioactive peptide that was no longer detectable when a 100-fold molar excess of cortisol was added to the photoreagents. Edman sequencing of tryptic peptides photolabeled with delta 6-[3H]cortisol or delta 6-[3H]corticosterone showed that these peptides correspond to residues 357-378 of the human CBG sequence. The major peak of radioactivity of these peptides was eluted at the 15th cycle (Trp-371). The radioactive tryptic peptides photolabeled with the four steroid photoreagents were subcleaved with alpha-chymotrypsin. The major part of radioactivity was recovered in the T-[*X]-S-S-L-F hexapeptide 370-375 (major peptide) and in the D-H-F-T-[*X]-S-S-L-F nonapeptide 367-375, at the second and fifth Edman cycles, respectively, whereas no PTH derivative could be identified at these cycles, thus suggesting Trp-371 as the main site of photolabeling for all tested photoreagents. Mass spectrometry of tryptic peptides photolabeled with delta 6-[3H]cortisol and delta 6-[3H]corticosterone and of chymotryptic peptides photolabeled with delta 6-[3H]cortisol, delta 6-[3H]corticosterone, and delta 6-[3H]progesterone showed molecular masses corresponding to the addition of delta 6-steroid photoreagents to the peptide.

Affinity Labels↗
PubMed1988

Purification and properties of squirrel monkey (Saimiri sciureus) corticosteroid binding globulin.

Corticosteroid binding globulin (CBG), a serum glycoprotein which binds glucocorticoids and progestins with high affinity, is widely distributed throughout the animal world. Although its charge and size characteristics have largely been conserved across species, we found the behavior of CBG in squirrel monkey (Saimiri sciureus) serum during fractionation by polyacrylamide gel electrophoresis or Sephadex chromatography was consistent with a molecule about twice the size of that found in most species. To more fully understand the basis for this difference, we purified the protein by sequential affinity and DEAE-Sepharose chromatographies. The final product was obtained in greater than 60% yield and was found to migrate as a single homogeneous band when examined by electrophoresis at pH 8.3 in polyacrylamide gels varying total acrylamide concentration or under conditions of severe protein overload. The steroid binding specificity of the purified protein was identical with that of the protein in the starting serum. The ultraviolet absorption spectrum of the isolated CBG-steroid complexes revealed that the protein had no pyridine nucleotide cofactor or nucleic acid. Amino acid analyses showed that the composition of the squirrel monkey protein is quite similar to that of CBG molecules from other species but distinct from albumins, hemoglobin, or rabbit progesterone receptor. In contrast to the single protein band observed following electrophoresis under normal conditions, separations in the presence of sodium dodecyl sulfate (SDS) resolved the pure protein into two bands: one at 54,000 daltons and one at 57,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1981

Steroid-protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity.

Reducing agents (dithiothreitol and beta-mercaptoethanol) significantly decrease the affinity constants of the human corticosteroid-binding globulin (CBG)-cortisol complex in proportion to their concentration; the resulting Ka values are more consistent than those obtained in the absence of the reductants. The effect is reversible. The equilibrium association constants of the CBG complexes with cortisol and progesterone show a relatively broad pH maximum between pH 8 and 11. In this pH range, cortisol was found to be bound more strongly than progesterone; this relationship is reversed around pH 6. The van't Hoff plot of the temperature effect on Ka of the CBG-cortisol complex (4-41 degrees C) exhibits a nonlinear, possibly biphasic temperature dependency. The shape of the van't Hoff plot was similar in the presence of mercaptoethanol. The association of cortisol and progesterone to human CBG at 4 and 37 degrees C is enthalpy driven, compensating for the unfavorable change in entropy. Studies with 47 steroids served to elucidate the influence on binding affinity of polar and nonpolar groups and other structural alterations. The contribution of specific structural changes in the steroid molecule to the free energy of binding can be calculated from the results. Important structures for optimal binding are the 20-oxo group, a 10 beta-methyl group, and a double bond at the 4 position. A complementary image of the binding site with respect to the nature of binding at various locations is proposed.

Animals↗