Glucocorticoid receptor interactions with glucocorticoids: evaluation by molecular modeling and functional analysis of glucocorticoid receptor mutants

Hammer, Stefanie; Spika, I.; Sippl, Wolfgang; Jessen, Gisela; Kleuser, Burkhard; Höltje, Hans‐Dieter; Schäfer‐Korting, Monika

doi:10.1016/s0039-128x(03)00030-8

Cited by 38 publications

(29 citation statements)

References 32 publications

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“…The endogenous, biologically active GC, cortisol, has a hydroxyl group at this position, while the biologically inactive form of the GC, cortisone, has a ketone group at this position ( fi g. 1 ). Binding of cortisol to the GR is thought to be dependent on the presence of the hydroxyl group at the 11 ␤ position [58] . Circulating plasma levels of free cortisol are approximately 100-fold lower than those of free cortisone, in large part because a signifi cant amount of cortisol remains reversibly bound to corticosteroid binding globulins (i.e., transcortin) and other plasma proteins [59] .…”

Section: Local Metabolism Of Glucocorticoidsmentioning

confidence: 99%

Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

et al. 2006

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It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11β-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species.

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Section: Local Metabolism Of Glucocorticoidsmentioning

confidence: 99%

Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

et al. 2006

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“…Recently, the precise structure of the ligand-binding domain of GR was revealed by the crystallisation of this domain [28] and independently by molecular modeling starting from the well-known ligand-binding domain of PR [29,30] . The C-terminal 12 helices of the GR fold into a three-layer sandwich which embeds the hydropho- bic pocket for the ligand.…”

Section: Receptor Structurementioning

confidence: 99%

“…As depicted in fi gure 2 , there is a close correlation of GR binding predicted by quantitative structure activity calculations and the binding data determined experimentally. Extending the set of 17 steroids [30] by another seven (table 1 ) the only exception is fl uticasone propionate, calculation of binding data is excluded since this agent is the only carbothiolate drug.…”

Section: Receptor Structurementioning

confidence: 99%

“…Composite GREs allow additional binding for non-receptor factors Table 1. Glucocorticoid receptor binding predicted from quantitative structure activity calculations and experimentally determined [30,81,82], IC 50 values for genomic and non-genomic effects in A549 cells [7] and relative activity in rheumatic diseases [13] [30]. [18] .…”

Section: Receptor Activation Response Elements Transactivation and mentioning

confidence: 99%

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Glucocorticoids for Human Skin: New Aspects of the Mechanism of Action

Schäfer‐Korting

Kleuser

Ahmed

et al. 2005

Skin Pharmacol Physiol

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Topical glucocorticoids have always been considered first-line drugs for inflammatory diseases of the skin and bronchial system. Applied systemically, glucocorticoids are used for severe inflammatory and immunological diseases and the inhibition of transplant rejection. Owing to the progress in molecular pharmacology, the knowledge of the mechanism of action has increased during the last years. Besides distinct genomic targets, which are due to the activation of specific cytoplasmatic receptors resulting in the (trans-) activation or (trans-) repression of target genes, there are non-genomic effects on the basis of the interference with membrane-associated receptors as well as with membrane lipids. In fact, various glucocorticoids appear to differ with respect to the relative influence on these targets. Thus, the extended knowledge of glucocorticoid-induced cellular signalling should allow the design and development of even more specifically acting drugs – as it has been obtained with other steroids, e.g. estrogens for osteoporosis prevention.

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“…The endogenous, biologically active GC, cortisol, has a hydroxyl group at this position, whereas the biologically inactive form, cortisone, has a ketone group at this position. High affinity binding of cortisol to the GC receptor (GR) is thought to depend on the presence of a hydroxyl group at the 11␤ position (23). Steroids containing a ketone group at the 11␤ position (i.e., cortisone and prednisone) tend to have extremely low agonist activity (7,17).…”

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confidence: 99%

11β-Hydroxysteroid dehydrogenase type 2 and the regulation of surfactant protein A by dexamethasone metabolites

Garbrecht

Schmidt²,

Krozowski³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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-Glucocorticoid (GC) metabolism by the 11␤-hydroxysteroid dehydrogenase (HSD) system is an important prereceptor regulator of GC action. The HSD enzymes catalyze the interconversion of the endogenous, biologically active GC cortisol and its inactive 11-dehydro metabolite cortisone. The role of the HSD enzymes in the metabolism of synthetic GCs, such as dexamethasone (Dex), is more complex. The human lung is a classic GC-sensitive organ; however, the roles of the HSD enzymes (HSD1 and HSD2) in the human lung are poorly understood. In the present study, we examined the expression of the HSD enzymes in human adult and fetal lung tissues and the human lung epithelial cell line NCI-H441. We observed that human adult and fetal lung tissues, as well as H441 cells, express HSD2 protein and that it is upregulated by Dex (10 Ϫ7 M). By contrast, HSD1 protein was undetectable. We also show that the Dexmediated regulation of surfactant protein A is attenuated by inhibition of HSD2 activity. Furthermore, we demonstrate that unlike the inactive, 11-dehydro metabolite of cortisol (i.e., cortisone), the 11-dehydro metabolite of Dex, 11-dehydro-Dex, competes for binding to the GC receptor (GR) in human lung epithelial cells and retains GR agonist activity. Together, these data suggest that differences exist in the biological activities of the metabolites of cortisol and Dex.

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Glucocorticoid receptor interactions with glucocorticoids: evaluation by molecular modeling and functional analysis of glucocorticoid receptor mutants

Cited by 38 publications

References 32 publications

Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

Glucocorticoids for Human Skin: New Aspects of the Mechanism of Action

11β-Hydroxysteroid dehydrogenase type 2 and the regulation of surfactant protein A by dexamethasone metabolites

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