RU 38486: Potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation

Moguilewsky, M.; Philibert, D.

doi:10.1016/0022-4731(84)90216-4

Cited by 374 publications

(126 citation statements)

References 21 publications

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“…A single injection of corticosterone to adrenalectomized animals, at the dose imitating the indomethacin-induced rise in corticosterone (7), restored blood glucose levels and significantly reduced gastric hypermotility and ulcerogenic responses to indomethacin, suggesting a role for glucocorticoids in gastric protection and glucose metabolism. This idea was also supported by the finding that the effects of corticosterone replacement in adrenalectomized rats were significantly antagonized by coadministration of RU-38486, a specific glucocorticoid receptor antagonist, which is known to bind with high affinity to type II glucocorticoid receptors (22) and may block the effect of glucocorticoids on glucose metabolism (13). These results are consistent with our previous findings that RU-38486 aggravated indomethacin-induced gastric lesions by antagonizing the beneficial influences of endogenous glucocorticoids released in response to indomethacin (10) and strongly suggest that lack of glucocorticoids may be a major mechanism for aggravation by adrenalectomy of indomethacin-induced gastric lesions.…”

Section: Discussionmentioning

confidence: 85%

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

Filaretova

Tanaka

Miyazawa

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats. Am J Physiol Gastrointest Liver Physiol 283: G1082-G1089, 2002. First published July 31, 2002 10.1152/ajpgi.00189.2002We investigated the mechanisms underlying the protective action of glucocorticoids against indomethacin-induced gastric lesions. One-week adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) were administered indomethacin (25 mg/kg sc), and gastric secretion (acid, pepsin, and mucus), motility, microvascular permeability, and blood glucose levels were examined. Indomethacin caused gastric lesions in sham-operated rats, with an increase in gastric motility and microvascular permeability as well as a decrease in mucus secretion. Adrenalectomy significantly worsened the lesions and potentiated these functional disorders. Glucose levels were lowered by indomethacin in sham-operated rats, and this response was enhanced by adrenalectomy. The changes observed in adrenalectomized rats were prevented by supplementations of corticosterone at a dose mimicking the indomethacin-induced rise in corticosterone, whereas the protective effect of corticosterone was attenuated by RU-38486, a glucocorticoid receptor antagonist. We conclude that the gastroprotective action of endogenous glucocorticoids may be provided by their support of glucose homeostasis and inhibitory effects on enhanced gastric motility and microvascular permeability as well as maintaining the production of mucus. gastric lesion; gastric microvascular permeability; gastric motility; mucus; acid and pepsin secretion

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Section: Discussionmentioning

confidence: 85%

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

Filaretova

Tanaka

Miyazawa

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Induction by dexamethasone or R 5020 takes place within a range of concentrations expected from the affinity of the receptors for these two ligands. Both the dexamethasone-and the R 5020-dependent expression are abolished by the presence of a 10-fold excess of the antiglucocorticoid and antigestagen RU 486 (17,18). Interestingly, estradiol has no effect on expression in MCF7 cells, even though this cell line possesses sufficient amounts of the estradiol receptor to allow induction of estrogen-responsive marker genes to occur (10,16).…”

Section: Resultsmentioning

confidence: 99%

A DNA sequence of 15 base pairs is sufficient to mediate both glucocorticoid and progesterone induction of gene expression.

Strähle

Klöck

Schütz

1987

Proc. Natl. Acad. Sci. U.S.A.

311

126

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To defmie the recognition sequence of the glucocorticoid receptor and its relationship with that of the progesterone receptor, oligonucleotides derived from the glucocorticoid response element of the tyrosine aminotransferase gene were tested upstream of a heterologous promoter for their capacity to mediate effects of these two steroids. We show that a 15-base-pair sequence with partial symmetry is sufficient to confer glucocorticoid inducibility on the promoter of the herpes simplex virus thymidine kinase gene. The same 15-base-pair sequence mediates induction by progesterone. Point mutations in the recognition sequence affect inducibility by glucocorticoids and progesterone similarly. Together with the strong conservation of the sequence of the DNA-binding domain of the two receptors, these data suggest that both proteins recognize a sequence that is similar, if not the same.The effect of steroid hormones on specific gene transcription is mediated by receptors to which the hormones bind with high selectivity and affinity. Activation of transcription results from binding of the hormone-receptor complex to specific sequences of inducible genes (1, 2). Surprisingly, it has been observed that fragments of the chicken lysozyme gene and of the long terminal repeat of mouse mammary tumor virus that confer glucocorticoid inducibility also allow progesterone induction (3, 4). The glucocorticoid and progesterone receptors bind to similar sequences within these fragments, suggesting that the binding sites may be closely related, but distinct (5, 6). Both types of receptors also bind to partially overlapping sequences in the rabbit uteroglobin gene (7,8). These sequences, however, have not been functionally characterized. To define the sequence requirements for specific binding of the glucocorticoid receptor and to determine the degree to which this sequence overlaps with the recognition sequence for the progesterone receptor, a minimal glucocorticoid response element (GRE) 15 base pairs (bp) in length was defined. This 15-bp sequence is part of the GRE region of the tyrosine aminotransferase (TAT) gene protected against DNase I digestion by the purified glucocorticoid receptor (9). We demonstrate here that the same 15-mer which confers responsiveness to glucocorticoids also mediates progesterone induction. Since point mutations in this 15-bp sequence affect inducibility by both steroids similarly, we suggest that the recognition sequences of the glucocorticoid and progesterone receptors are similar, if not identical. MATERIALS AND METHODSPlasmid Constructions. Oligonucleotides were prepared with an Applied Biosystems 380A DNA synthesizer and purified as recommended by the manufacturer. Annealing of the complementary strands, which generated BamHI or Xba I cohesive ends, and cloning upstream of the herpes simplex virus thymidine kinase (TK) promoter in pBLCAT2 (10) were done by standard procedures (11). pBLCAT2 contains the complete TK promoter (-105 to +62) linked to the chloramphenicol acetyltransferase (CAT) co...

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“…However, most cells die in the tissue by apoptosis, and the dying cells are rapidly removed by phagocytosis. It has been suggested that endogenous glucocorticoids are important mediators of the thymic negative selection event [40, 411 as thymocytes, both in vitro and in vivo, are very sensitive to glucocorticoids [40, 421 whose effects can be inhibited by the antagonist RU486 [43,441. Preliminary evidence also suggests formation of deoxycorticosterone in TEC cells [ 5 ] demonstrating the capacity of these cells to metabolise cholesterol.…”

Section: Discussionmentioning

confidence: 99%

7α‐Hydroxylation and 3‐Dehydrogenation Abolish the Ability of 25‐Hydroxycholesterol and 27‐Hydroxycholesterol to Induce Apoptosis in Thymocytes

Zhang

Xue

Jondal

et al. 1997

European Journal of Biochemistry

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Oxygenated derivatives of sterols (oxysterols), including 25-hydroxycholesterol and 27-hydroxycholesterol, have immunosuppressive effects. Oxysterols can directly induce apoptosis in immature thymocytes, cells which are inherently sensitive to induction of programmed cell death. For that reason, the metabolism of 25-hydroxycholesterol and 27-hydroxycholesterol in mouse thymus has been studied. When incubated with thymic tissue, both oxysterols were found to be 7a-hydroxylated with subsequent oxidation to 7a-hydroxy-3-0x0-A4 steroids. A minor fraction of 27-hydroxycholesterol was also metabolised to 3/?-hydroxy-5-cholestenoic, 3~,7a-dihydroxy-5-cholestenoic and 7a-hydroxy-3-oxo-4-cholestenoic acids. The 7a-hydroxylase was found to be localised to the thymic epithelial cells and the reaction was stimulated by interleukin-la and inhibited by metyrapone and RU486. In contrast to 25-hydroxycholesterol and 27-hydroxycholesterol, the 7a-hydroxylated metabolites, 7a,25-dihydroxycholesterol, 7a,25-dihydroxy-4-cholesten-3-one and 7a,27-dihydroxy-4-cholesten-3-one did not induce thymocyte apoptosis. The results suggest that 7a-hydroxylation may be of regulatory importance, possibly by protecting the developing thymocytes against toxic effects by oxysterols.Keywords: 25-hydroxycholesterol ; 27-hydroxycholesterol ; 7a-hydroxylation; thymocytes; apoptosis.In thymus, the developing T cell system undergoes a process of self-recognition [I]. Immature, cortical double-positive (CD4+/CD8+) thymocytes are positively selected by T-cell-receptor recognition of self major histocompatibility complex antigens 121. Most developing thymocytes lack this capacity and are consequently negatively selected by induction of programmed cell death, or apoptosis [3, 41. Immature thymocytes are inherently sensitive to induction of apoptosis by many different signals, including endogenous glucocorticoids which might be important in the negative selection process [S].Oxysterols have a wide spectrum of biological activities including the capacity to depress the immune system (for a review see [6]). 25-Hydroxycholesterol has been shown to induce apoptosis of thymocytes in an independent way from that mediated by glucocorticoids [7 -91. Both 25-hydroxycholesterol and 27-hydroxycholesterol can be formed from cholesterol in the liver and extrahepatic tissues, in reactions catalysed by a sterol 27-hydroxylase or 25-hydroxylase [ 10-141. We and others have recently found that 25-hydroxycholesterol and 27-hydroxycholesterol can be metabolised by 7a-hydroxylation in several tissues and cells 115-221. The aim of the present study was to investigate if this reaction also occurs in thymus and to determine the relative potencies of the oxysterols and their metabolites as inducers of apoptosis in thymocytes. MATERIALS AND METHODSChemicals. All solvents were of analytical grade and were redistilled. Dimethylsulfoxide was purchased from Fluka Chemie AG. Hydroxypropyl-a-cyclodextrin was from Aldrich and octadecylsilane-bonded silica (Preparative C ,x) from Waters Ass...

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RU 38486: Potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation

Cited by 374 publications

References 21 publications

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

A DNA sequence of 15 base pairs is sufficient to mediate both glucocorticoid and progesterone induction of gene expression.

7α‐Hydroxylation and 3‐Dehydrogenation Abolish the Ability of 25‐Hydroxycholesterol and 27‐Hydroxycholesterol to Induce Apoptosis in Thymocytes

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