Showing papers on "Glucocorticoid published in 1979"

Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation.

Abstract: Although it has been clearly established that glucocorticoids inhibit mitogen- or antigen-induced lymphocyte proliferation, the mechanism underlying this effect has remained ill-defined. Recently, it has become evident that T cell proliferation is mediated by a soluble T cell growth factor (TCGF) released by mitogen/antigen stimulated T cells. Therefore it seemed probable that the inhibitory effects of glucocorticoids were manifested either at the level of TCGF production or at the level of the activated T lymphocyte. We found that differentiated cytolytic T lymphocytes harvested from TCGF-dependent long-term culture were only mildly sensitive to inhibitory effects (25 to 30% inhibition) of glucocorticoids as measured by decreased cellular proliferation and the incorporation of tritiated thymidine. The degree of inhibition observed was most probably mediated through glucocorticoid receptors in that the half maximal inhibitory glucocorticoid concentration correlated with half-maximal glucocorticoid receptor saturation. In contrast, we found that mitogen-induced TCGF production and T cell proliferation were completely inhibited by pharmacologic concentrations of dexamethasone (10 -6 M). Finally, the TCGF supplementation of mitogen-stimulated cultures treated with maximal inhibitory concentrations of dexamethasone resulted in complete amelioration of glucocorticoid suppression. These results indicate that a major mechanism of glucocorticoid-mediated immunosuppression may occur at the level of the TCGF-producing cell, resulting in the control of clonal expansion of activated T cells via inhibition of TCGF production.

A Syndrome of Apparent Mineralocorticoid Excess Associated with Defects in the Peripheral Metabolism of Cortisol

Abstract: A syndrome is described whose features, suggestive of primary mineralcorticoid excess, included hypertension, hypokalemia, low PRA, and responsiveness to spironolactone. Aldosterone levels were subnormal but as yet there has been no evidence of overproduction of other mineralocorticoids by chemical analysis or by bioassay of plasma and urinary extracts. The steroidal abnormalities that were observed involved peripheral matabolism rather than secretion. One patient exhibited a transient delay in reduction of the 3-keto group in the A ring, and both patients exhibited a decrease in the metabolism of cortisol to biologically inactive cortisone. This was shown by the marked decrease in the excretion of urinary metabolites bearing an 11-keto group and a decrease in the oxidation of 11 alpha-[3H]cortisol to tritiated water. The defect appeared not to be a deficiency of the 11 beta-oxidoreductase system itself, since the reverse reaction of conversion of cortisone to cortisol proceeded normally, but, rater, an alteration in the equilibrium position of 11 beta-oxidoreduction in favor of the reduced form. This was also expressed by a prolongation of the half-time of disappearance of cortisol. The decrease in the MCR permitted the maintenance of normal cortisol plasma levels and normal glucocorticoid function at a diminished rate of secretion. The decreased rate of conversion of cortisol to cortisone serves as a biochemical marker of this hypertensive syndrome.

Glucocorticoid-Induced Inhibition of T Cell Growth Factor Production: II. The Effect on the in Vitro Generation of Cytolytic T Cells

Abstract: The previous communication presented data detailing that glucocorticoid hormones exhibited slight but significant inhibitory effects on the proliferation of cytolytic T cells maintained in long-term T cell growth factor (TCGF)-dependent cultures. However, most importantly, glucocorticoids were shown to inhibit T-lymphocyte proliferation via a profound effect on TCGF production. Addition of exogenous TCGF to glucocorticoid-treated human, mouse, or rat T cell mitogen-stimulated lymphocytes restored normal levels of proliferation. These observations led us to propose that the immunosuppressive effects of glucocorticoid hormones were mediated by controlling the production of the T cell proliferation-inducing agent, TCGF. Results of experimentation detailed in this communication provide further evidence in support of this hypothesis. We found that although glucocorticoid hormones had little effect on the cytolytic reactivity of T cells harvested from TCGF-dependent culture, treatment of mixed lymphocyte cultures (MLC) with identical glucocorticoid hormone concentrations completely abrogated in situ TCGF production and alloantigen-directed cytolysis. The inhibitory effects of glucocorticoids in MLC could be eliminated once again simply by the delayed addition of exogenous TCGF. These observations coupled with those detailed in the previous report provide evidence that, rather than effecting lysis of potentially reactive mature lymphocytes, glucocorticoids influence the development of T cell-mediated immune reactivity by inhibiting TCGF production, which in turn serves to inhibit the clonal expansion of activated T cells.

Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line.

Abstract: Growth of a human leukemic T-cell line (CEM C7) in 10(-6) M dexamethasone results in inhibition of growth and rapid loss of cell viability after a delay of approximately 18 to 24 hours. Analysis of dexamethasone-treated cells by flow-microfluorometry showed that they were arrested in the G1 phase of the cell cycle. Loss of cell viability began at the same time as G1 accumulation was first detectable, and 20% of all cells were found to be blocked in G1 at this time suggesting that loss of viability and G1 arrest were coincident events. Half-maximal and maximal effects on both viability and G1 arrest after 48 hours in steroid were nearly identical with respect to steroid concentration and corresponded to half-maximal and full occupancy of glucocorticoid specific receptor by hormone, consistent with a glucocorticoid receptor mediated mechanism for both phenomena. Most non-viable cells were arrested in G1, and accumulation of cells in G1 was irreversible; removal of steroid in the presence of colcemid did not result in a decreased fraction of G1 cells. Furthermore, dexamethasone treatment did not protect cells against the effects of 33258 Hoechst-amplified killing of bromodeoxyuridine substituted cells exposed to light. These results show that dexamethasone arrests these leukemic cells in G1 and strongly suggest that dexamethasone-treated cells are killed upon entry into G1.

Glucocorticoid Receptors and Actions in Subpopulations of Cultured Rat Bone Cells: MECHANISM OF DEXAMETHASONE POTENTIATION OF PARATHYROID HORMONE-STIMULATED CYCLIC AMP PRODUCTION

Abstract: We have previously shown that bone cells possess glucocorticoid receptors and that, in addition to being inhibitory to cell growth, glucocorticoid treatment potentiates the ability of parathyroid hormone (PTH) to stimulate cyclic AMP (cAMP) formation. This study extends those observations to specific subpopulations of bone cells and explores the mechanism of the cAMP augmentation. Subpopulations of cultured bone cells derived from 20-d-old fetal rat calvaria were enriched for "osteoblast-like" (OB) and "osteoclast-like" (OC) cells by sequential collagenase digestion. OC cells released during the first 30 min of collagenase digestion were characterized by low alkaline phosphatase activity, a cAMP response to salmon calcitonin (CT), but only a small cAMP response to bovine PTH. In contrast, OB cells released between 30 and 120 min of collagenase digestion, possessed high alkaline phosphatase activity, responded with a large cAMP rise to PTH, but exhibited no response to CT. Glucocorticoid receptors, with similar properties, were demonstrated in both populations (K(d) congruent with 5 nM, N(maximum) congruent with 400 fmol/mg cytosol protein). Dexamethasone equivalently inhibited cell growth and alkaline phosphatase activity in both populations. Dexamethasone potentiation of cAMP generation occurred after PTH but not CT stimulation. A greater enhancement of cAMP generation observed in OB cells appears to result from two glucocorticoid actions: (a) stimulation of adenylate cyclase and (b) inhibition of phosphodiesterase. Only the latter mechanism was found in OC cells. Dexamethasone-treated cells showed an increase in both sensitivity and maximal response of cAMP to PTH. The possible relationship of these actions to the mechanism of glucocorticoid-induced osteopenia is discussed.

Human adipose tissue in culture. VIII. Studies on the insulin-antagonistic effect of glucocorticoids

Abstract: Biopsies of human adipose tissue were maintained for 1 wk in vitro with physiologic (1.5–30 × 10 −8 M ) or pharmacologic (300 × 10 −8 M ) concentrations of hydrocortisone or 1000 μU/ml insulin, or both. After this period, the explants were washed and incubated for 2 hr according to techniques generally used to study fat cell metabolism. Physiologic concentrations of hydrocortisone mainly exert an insulin antagonistic effect. Thus, the long-term effects of insulin in increasing lipolysis, as well as glucose metabolism to triglycerides, were reduced, as were the acute effects of insulin on these parameters. At these concentrations, the glucocorticoid itself did not influence the basal metabolic rates when due consideration was given to simultaneous changes in mean fat cell size. At higher concentrations, which may easily be reached during nonspecific glucocorticoid therapy, the glucose metabolism was reduced. Hydrocortisone decreased the number of insulin receptors. However, this cannot solely explain the insulin-antagonistic effect, since it was not overcome by a supramaximal concentration of insulin. Insulin and hydrocortisone together increased the lipoprotein lipase (LPL) activity several times. The resultant changes in LPL appear to depend upon the insulincorticosteroid ratio.

Stimulation of the pituitary-adrenocortical axis by nerve growth factor.

Abstract: Nerve growth factor (NGF) is a protein essential for the development and maintenance of the peripheral sympathetic nervous system, causing responsive neurones to increase in size and to extend neurites. Biochemically, the selective induction of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase key enzymes in catecholamine biosynthesis is one of its most characteristic effects. Both the morphological and biochemical effects are modulated by glucocorticoids, suggesting a close relationship between specific effects of NGF and hormone action. NGF has been shown to induce an increase in adrenal cyclic AMP in intact but not in hypophysectomised rats, and so we have looked directly at the effect of systemic administration of NGF on the hypothalamo-pituitary-adrenal axis. We report here that NGF induced an enhanced secretion of adrenocorticotropin (ACTH) and a prolonged increase in plasma glucocorticoid concentration after intravenous (i.v.) injection. Such effects could have important implications for the biological activity of NGF.

Regulation of gluconeogenesis by glucocorticoids.

Abstract: 1 Regulation of gluconeogenic substrate supply and modulation of the gluconeogenic pathway in the liver are both important in the control of gluconeogenesis by glucocorticoids 2 Adrenal deficiency decreases the release of gluconeogenic and other amino acids from skeletal muscle during starvation The effect is reversed by glucocorticoid replacement The changes in amino acid release are accompanied by similar alterations in tissue amino acid levels and are not explained by alterations in net protein breakdown Glucocorticoids do not alter protein catabolism and cause a small inhibition of protein synthesis The biochemical alterations underlying the changes in amino acid metabolism induced by these steroids remain to be elucidated Glucocorticoids may also regulate the supply of gluconeogenic substrates through permissive effects on the lipolytic action of catecholamines and other hormones in adipose tissue and on the glycogenolytic action of catecholamines on skeletal muscle 3 Glucocorticoids are required for the increases in gluconeogenesis in starvation and diabetes Part of their action is exerted directly on the liver and appears to involve modulation of P-enlopyruvate carboxykinase levels Glucocorticoids increase the synthesis of this enzyme apparently through effects at the level of transcription 4 Glucocorticoids exert permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine The steroids are not required for cAMP generation or protein kinase activation by these hormones, but appear to act by maintaining the responsiveness of certain enzymes to the effects of the cAMP and alpha-adrenergic systems It is proposed that this involves the maintenance of a normal intracellular ionic environment

The role of corticosterone in the loss in immune function in the zinc-deficient A/J mouse.

Abstract: Previous studies from this laboratory have shown that zinc deficiency causes rapid atrophy of the thymus with subsequent loss of T-cell helper function in the young adult A/J mouse. The purpose of this investigation was to determine if zinc deficiency constituted a chronic stress on the mouse leading to the elevation of glucocorticoid levels which is known to destroy thymic lymphocytes. The results of these experiments indicate that zinc-deficient mice indeed have increased levels of plasma corticosterone (115 mug/100 ml plasma) compared to mice fed zinc-adequate diets (40 mug/100 ml plasma). A significant reduction in T-cell helper function, which occurred 4 days after this rise in steroid concentration, suggests that corticosterone may contribute to the loss in immunity; however, about half of the total loss in T-cell helper function occurred prior to the increase in plasma corticosterone and was due to other factors associated with the lowered zinc levels.

Adrenal steroids indirectly modulate morphine and beta-endorphin effects.

Abstract: The pharmacological effects of morphine or the postulated physiological opiate, beta-endorphin, were compared in adrenalectomized and sham control animals. Pretreatment of adrenalectomized rats and mice with the synthetic glucocorticoid dexamethasone 2 hr before opiate injections abolished the adrenalectomy-induced sensitization to parenteral opiates. This effect of dexamethasone was completely blocked by cycloheximide, a protein-synthesis inhibitor. After parenteral injection ot tritiated morphine, total tritium counts in the blood and brains of adrenalectomized mice were greater than in sham controls; this effect was also blocked by dexamethasone pretreatment. Administration of SKF 525-A before morphine produced results which suggest that this putative inhibitor of the mixed-function oxidase metabolizing enzyme system also alters opiate potency. Collectively, these studies provide evidence that adrenalectomy causes a decrease in morphine metabolism which enhances the parenteral potency of this opiate through increased bioavailability. Furthermore, the dexamethasone reversal of this effect appears to depend upon its de novo induction of protein components of the opiate-metabolizing system. The possibility that a physiological interplay between endorphins and corticosteroids exists is suggested by the dexamethasone blockade of both the pharmacological effects and the toxicity of intravenous beta-endorphin in adrenalectomized mice.

Thyroid axis in patients with Cushing's syndrome.

Abstract: Thyroid hormone values and serum thyrotropin (thyroidstimulating hormone [TSH]) responses to the intravenous administration of 400 μg of protirelin were determined in ten patients with Cushing's syndrome and in ten matched normal subjects. In patients with Cushing's syndrome, the serum thyroxine (T 4 ) level was mildly depressed and free T 3 level was normal. The mean ( ± SD) concentrations of serum triiodothyronine (T 3 ) and free T 3 were both reduced in patients compared with normal subjects ( P P 3 and free T 3 levels are due to a glucocorticoid suppressive effect on the peripheral conversion of T 3 to T 3 . The protirelin test is of limited value in assessing the thyroid status because the response of TSH is frequently blunted or absent due to glucocorticoid excess. ( Arch Intern Med 139:767-772, 1979)

Sex Hormone and Glucocorticoid Receptors in the Bursa of Fabricius of Immature Chicks

Abstract: Estrogen, androgen, progestin, and glucocorticoid binding was measured in the immature chick bursa of Fabricius. Studies with whole bursal cytosol indicated the presence of distinct and noninteracting estradiol, dihydrotestosterone, progesterone, and dexamethasone receptors with mean dissociation constants of 0.1, 0.3, 7.8, and 12 nM and average binding site concentrations of 1.9, 13.6, 42, and 520 fmoles/mg protein, respectively. Binding to saturable sites was specific for steroids with estrogen, androgen, progestin, or glucocorticoid activity. For example, estrone and diethylstilbestrol competed with estradiol, whereas progesterone, dihydrotestosterone, and dexamethasone did not. Similarly, testosterone competed for dihydrotestosterone binding, whereas estradiol, progesterone, and dexamethasone competed very little. In the presence of 5 µM cortisol, progestosterone binding was competed for by the anti-progestin R-5020, but not by dexamethasone, estradiol, and dihydrotestosterone. Competition for dexamethasone binding was observed with cortisol and corticosterone but not with estradiol, dihydrotestosterone, and progesterone. When cytosol was prepared from bursal cell pellets that were predominantly lymphoid in nature, glucocorticoid but not estrogen, androgen, or progestin binding was identified. Since only glucocorticoid binding was found, it suggests that estrogen, androgen, and progestin receptors are present in epithelial cells of the bursa. Binding of dexamethasone in intact cells to cytosol and nuclear forms of the receptor complex and the temperature-dependent translocation of receptor complex from the cytosol to the nucleus were also shown. The results presented indicate that estrogens, androgens, progestins, and glucocorticoids interact with cells in the bursa of Fabricius at physiologic concentrations.

Influences of adrenocortical hormones on pituitary and brain function.

Abstract: Adrenocortical secretions influence neuroendocrine function and behavior, and it is possible to recognize separate physiologic actions of gluco- and mineralocorticoids. The search for neuroanatomical sites and cellular modes of adrenocorticoid action has revealed a system of putative glucocorticoid receptors in neurons of the hippocampus, septum, amygdala, and entorhinal cortex, and in the pituitary. No part of the brain is totally devoid of receptor activity, however, and glial cells may also contain glucocorticoid receptors. Mineralocorticoid receptors are less well characterized neuroanatomically or biochemically. One reason for this is the considerable degree to which both gluco- and mineralocorticoids bind to both classes of receptors in vitro. Another reason may be the overwhelming quantitative predominance of glucocorticoid over mineralocorticoid receptors in neural tissue. Glucocorticoid receptors of the pituitary, which have a high avidity for dexamethasone, appear to participate in the delayed negative feedback effects of glucocoticoids. Functional correlates of neural glucocorticoid receptors remain to be clearly established. Among the possibilities are several reported effects on hippocampal neural activity that have an onset latency of 20--30 min and a duration of several hours. The relative rapidity of such effects does not preclude genomic mediation, as genomic effects of glucocorticoids on thymus lymphocytes have been detected within as little as 15 min of steroid application [117]. What are not so far explained by the intracellular receptor mechanism are the extremely rapid effects of glucocorticoids such as the rate-sensitive negative feedback on CRF and ACTH secretion. These may involve a direct action of the steroid on cell membranes in the pituitary and hypothalamus.

Glucocorticoids and immune responses

Abstract: We describe a series of investigations on mechanisms of antiinflammatory and immunosuppressive actions of glucocorticoids. Glucocorticoid receptors and primary mechanisms of action have been studied with isolated rat thymus cells. When added to these cells glucocorticoids immediately form cytoplasmic hormone-receptor complexes which after activation bind to the nuclei where they apparently induce mRNA for specific proteins that rapidly inhibit glucose transport and acetate incorporation into lipids. Protein and RNA metabolism are inhibited more slowly and eventually the cells die. With normal peripheral human lymphocytes, similar but slower effects are produced. A dramatic increase in receptor sites per cell is seen in lymphocytes stimulated with concanavalin A or antigen. This increase is probably associated with preparation for mitosis. We do not find, contrary to widespread belief, that these stimulated cells are insensitive to glucocorticoids. Such insensitivity has been invoked to explain the insensitivity to glucocorticoid suppression of secondary compared to primary immune responses. An alternative explanation emerges from our experiments with T-cell growth factor. T-cell growth factor, produced by mitogen or antigen stimulated spleen cells, is necessary for the proliferation of T-lymphocytes in culture and may be responsible for clonal expansion of antigen-responsive T-cells. Treatment of Con A-stimulated rat spleen cells or human peripheral mononuclear cells with 100 nM dexamethasone inhibits the production of the growth factor by 95%. This effect is specific for glucocorticoids. Addition of T-cell growth factor completely reverses the inhibition by glucocorticoid of mitogen-induced blastogenesis. We propose that the inhibitory actions of glucocorticoids on antigen- or mitogen-induced T-cell blastogenesis are related to inhibition of production of T-cell growth factor and that the reason the primary immune response is more sensitive to glucocorticoids is that by inhibiting production of T-cell growth factor, glucocorticoids block the clonal expansion necessary to amplify the primary response. We have also studied effects of glucocorticoids on Fc receptors, which play important roles in phagocytosis and other aspects of immune responses. Treatment of the human progranulocytic cell line HL-60 with dexamethasone for 72 hours reduces by 35-50% the Fc receptors per cell with no effect on cell viability or proliferation and slight increase in leucine incorporation. The effect is specific for glucocorticoids. These findings indicate that an important component in glucocorticoid-induced immunosuppression may be a reduction in Fc receptors, and with the results on T-cell growth factor, suggest that glucocorticoids regulate immune processes via effects on lymphokines and other immunologically important proteins.

Glucocorticoids regulate the concentration of 1,25-dihydroxycholecalciferol receptors in bone

Abstract: THE results of a study of high-affinity glucocorticoid and 1,25-dihydroxycholecalciferol (1,25(OH)2D3) binding in cytosol from fetal rat calvaria cultured for up to 48 h at 37°C are presented. The binding of glucocorticoids was found to be stable in short-term culture, whereas that for 1,25(OH)2D3 declined rapidly, was almost undetectable at 24 h and had disappeared by 48 h. Furthermore, low concentrations of cortisol (10−8 to 10−6 M) added to the culture medium had a dramatic effect on the persistence of high affinity 1,25(OH)2D3 binding. In the presence of cortisol there was dose-dependent preservation of most of the binding of 1,25(OH)2D3 in the cytosol. 1,25(OH)2D3 is a potent agent in inducing bone resorption in vitro and these data suggest that glucocorticoids may exert part of their effects on calcium metabolism and bone in vivo by directly regulating the turnover of cytosol 1,25(OH)2D3 receptors in one or more types of bone cell.

Delineation of the Glucocorticoid-Sensitive Period of Intestinal Development in the Rat*

Abstract: Jejunal sucrase has been used as a marker for intestinal development. The effects of sequential adrenalectomy and sequential administration of hydrocortisone have led to the conclusion that the glucocorticoid sensitivity of the jejunum ceases abruptly at a postnatal age of 17–18 days. Adrenalectomy on day 17 or earlier resulted in significant depression of the usual developmental rise of sucrase activity, whereas adrenalectomy on days 18, 21, or 28 or in adults had no effect on sucrase activity. In contrast, the effect of adrenalectomy on body weight was similar at all ages studied. When hydrocortisone (50 μg/g BW) was administered to intact animals on day 15 or 16, it caused significant elevation of sucrase activity but, when administered on day 17,18, or 28, there was no difference between control and treated animals. Since adrenalectomy on day 15 delayed weaning, it was possible that the glucocorticoid dependence of the younger animals was mediated by effects on feeding behavior. However, a further stu...

The Ontogony of the Human Placental Glucocorticoid Receptor and Inducibility of Heat-Stable Alkaline Phosphatase*

Abstract: The human placenta was found to contain a cytosol receptor for glucocorticoids. The concentration of this receptor in term placenta was 27-fold higher than that found in cytosol from first trimester placenta. The levels of cytosol glucocorticoid receptor in three trophoblastic cell lines (JAr, BeWo, and JEG) were also determined and all were found to be low. The ability of prednisolone, a potent glucocorticoid, to stimulate heat-stable alkaline phosphatase activity found in these cells was tested. Although control experiments demonstrated that the conditions were adequate to stimulate HeLa cell alkaline phosphatase, none of the trophoblastic lines responded to prednisolone administration. This result may be explained by the observation that the JAr cells lacked any detectable glucocorticoid receptor and the receptor levels in cytosol prepared from JEG and BeWo cells were 12% and 2%, respectively, of those measured in HeLa cytosol. Our studies also suggest that the increase in serum levels of heat-stable a...

Direct Inhibition of Growth and Antagonism of Insulin Action by Glucocorticoids in Human Breast Cancer Cells in Culture

Abstract: We have examined the interaction of dexamethasone with the ZR75-1 human breast cancer cell line to determine if glucocorticoids might directly inhibit growth of breast cancer cells. Growth of these cells in serum-free medium was stimulated significantly by physiological concentrations of insulin (0.1 to 1.0 nm). Pharmacological concentrations of dexamethasone (10 nm) reduced cell number below that found in controls and nearly abolished the effect of insulin after several days in culture. Thymidine and uridine, but not leucine, incorporation into macromolecules or acetate incorporation into fatty acids were similarly inhibited by dexamethasone in the presence or absence of insulin. Dexamethasone did not inhibit insulin effects by altering insulin receptor affinity or concentration, as determined by Scatchard analyses of insulin binding. Net thymidine uptake into the trichloroacetic acid-soluble fraction of the cell was stimulated by insulin and inhibited by dexamethasone. Dexamethasone also inhibited thymidine kinase activity in both control and insulin-stimulated cells. These data suggest multiple potential sites of glucocorticoid action that directly oppose the effects of insulin. They also suggest that glucocorticoids have a direct inhibitory effect on proliferation of human breast cancer cells, which may help explain breast tumor regression following pharmacological glucocorticoid therapy.

Glucocorticoid Regulation of Prolactin Receptors on Mammary Cells in Culture

Abstract: Mouse mammary epithelial cultures were examined for the ability to specifically bind [125I]PRL after cultivation on floating collagen gels. Corticosterone, particularly hydrocortisone, were effective in increasing the ability of mouse mammary cells to bind [125I]PRL. The absence of a glucocorticoid in the medium resulted in a loss of PRL binding during the 3 days in culture. 17β-Estradiol, progesterone, and aldosterone at equal molar concentration had no or only a small effect in increasing [125I]PRL binding.

17 beta-carboxamide steroids are a new class of glucocorticoid antagonists.

Abstract: GLUCOCORTICOID hormones exert many of their effects by modifying the activity of certain enzymes in target tissues, probably as a result of alterations in gene expression1. Experimental models have been developed in which enzyme induction by various steroids correlates well with their anti-inflammatory, thymolytic and glycopexic properties. This is the case for tyrosine transaminase in cultured rat hepatoma (HTC) cells2,3. Studies in this system showed that, in addition to glucocorticoid agonists, partial agonists and antagonists could be identified4. The latter compete with agonists for binding to the intracellular glucocorticoid receptor but do not trigger the glucocorticoid effect5. Compounds which specifically antagonise glucocorticoid action at the target cell would be useful for the treatment of certain diseases characterised by excessive production of gluco-corticoids1 and for further studying the molecular mechanism of action of these hormones. However, unlike anti-androgens and anti-oestrogens6, the only known glucocorticoid anatagonists are natural steroid hormones (such as progesterone and testosterone) or their analogues, which interact with their own receptors and plasma binding proteins and are therefore not very specific. We report here that new derivatives of dexamethasone, a specific glucocorticoid agonist which does not bind to rat or human plasma transcortin5, can block the induction of tyrosine transaminase in HTC cells.

Comparison of the Effects of ‘Glucocorticoid’ And ‘Mineralocortocoid’ Infusions on Blood Pressure in Sheep

Abstract: It is generally believed that adrenal steroid hypertension is due to the ‘mineralocorticoid’ and/or ‘glucocorticoid’ activities of the steroid(s). The present study examines the blood pressure and metabolic effects of steroid hormone infusion in intact conscious sheep to assess the relative contributions of ‘glucocorticoid’ and ‘mineralocorticoid’ activity.Cortisol at 5 mg/h increased mean arterial pressure (MAP) but the effect was small (MAP + 10 mm Hg on day 5). This rate of infusion produces blood cortisol levels appropriate for maximal ACTH stimulation. Cortisol at 20 mg/hr produced hypertension (MAP + 25 mm Hg on day 5, p lt;0.01) but also produced the ‘mineralocorticoid’ effect of severe hypokalaemia.