Metabolism of Synthetic Corticosteroids by 11β-hydroxysteroid-Dehydrogenases in Man

Diederich, Sven; Hanke, Bert; Burkhardt, Patrick; Müller, Markus; Schöneshöfer, M.; Bähr, V.; Oelkers, W.

doi:10.1016/s0039-128x(98)00039-7

Cited by 48 publications

(42 citation statements)

References 29 publications

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“…Interestingly, there is evidence that the influence of the 11␤-HSD system on dexamethasone is different from the effects on natural glucocorticoids. For example, 11␤-HSD2 actively catalyzes the oxidoreduction of 11-dehydrodexamethasone to active dexamethasone but does not oxidoreduce cortisone to cortisol (11). In addition, there is recent evidence that the 11-dehydro form of dexamethasone (generated by 11␤-HSD2) is biologically active (as opposed to the 11-dehydro form of natural glucocorticoids) (18).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Itagaki

Menconi

Antoniu

et al. 2010

American Journal of Physiology-Cell Physiology

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Hasselgren PO. Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A 2-dependent mechanism. Am J Physiol Cell Physiol 298: C1127-C1139, 2010. First published January 27, 2010; doi:10.1152/ajpcell.00309.2009.-Muscle wasting in various catabolic conditions is at least in part regulated by glucocorticoids. Increased calcium levels have been reported in atrophying muscle. Mechanisms regulating calcium homeostasis in muscle wasting, in particular the role of glucocorticoids, are poorly understood. Here we tested the hypothesis that glucocorticoids increase intracellular calcium concentrations in skeletal muscle and stimulate storeoperated calcium entry (SOCE) and that these effects of glucocorticoids may at least in part be responsible for glucocorticoid-induced protein degradation. Treatment of cultured myotubes with dexamethasone, a frequently used in vitro model of muscle wasting, resulted in increased intracellular calcium concentrations determined by fura-2 AM fluorescence measurements. When SOCE was measured by using calcium "add-back" to muscle cells after depletion of intracellular calcium stores, results showed that SOCE was increased 15-25% by dexamethasone and that this response to dexamethasone was inhibited by the store-operated calcium channel blocker BTP2. Dexamethasone treatment stimulated the activity of calcium-independent phospholipase A 2 (iPLA2), and dexamethasone-induced increase in SOCE was reduced by the iPLA 2 inhibitor bromoenol lactone (BEL). In additional experiments, treatment of myotubes with the store-operated calcium channel inhibitor gadolinium ion or BEL reduced dexamethasone-induced increase in protein degradation. Taken together, the results suggest that glucocorticoids increase calcium concentrations in myocytes and stimulate iPLA 2-dependent SOCE and that glucocorticoid-induced muscle protein degradation may at least in part be regulated by increased iPLA 2 activity, SOCE, and cellular calcium levels. glucocorticoids; muscle; wasting MUSCLE WASTING, mainly reflecting stimulated degradation of myofibrillar proteins, is commonly seen in patients with sepsis, severe injury, and cancer (24, 52). Loss of muscle mass also occurs in patients with muscular dystrophy (30, 31). In previous studies, we found evidence (4, 15, 79) that sepsis-induced muscle proteolysis was associated with increased uptake and tissue levels of calcium in skeletal muscle. Additional reports suggest that muscle atrophy caused by other catabolic conditions, including denervation, burn injury, and muscular dystrophy, is also associated with increased tissue concentrations of calcium (2,3,10,17,64,73). These observations are significant because calcium is an important regulator of muscle protein balance and may link systemic catabolic responses to stimulated protein breakdown in skeletal muscle (16,34,50). The mechanisms regulating calcium entry and cellular levels of calcium in muscle-wasting conditions are not known.Glucocorticoids are prom...

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Section: Discussionmentioning

confidence: 99%

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Itagaki

Menconi

Antoniu

et al. 2010

American Journal of Physiology-Cell Physiology

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“…These prematurely born infants experience respiratory distress syndrome (RDS) and require mechanical lung ventilation, which itself can cause additional lung diseases. RDS is a major cause of infant mortality and is among the most common and costly medical problems afflicting prematurely born infants (National Institutes of Health Consensus Panel, 1995).Synthetic fluorinated corticosteroids exhibit transplacental passage when administered to pregnant women because of low affinity for maternal corticosteroid binding globulin (CBG) and poor breakdown by placental steroid metabolizing enzymes (Pugeat et al, 1981;Diederich et al, 1998). DEX, in the form of its soluble phosphate ester prodrug, is administered prenatally to induce fetal lung maturation in women at risk of preterm delivery.…”

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confidence: 99%

“…Synthetic fluorinated corticosteroids exhibit transplacental passage when administered to pregnant women because of low affinity for maternal corticosteroid binding globulin (CBG) and poor breakdown by placental steroid metabolizing enzymes (Pugeat et al, 1981;Diederich et al, 1998). DEX, in the form of its soluble phosphate ester prodrug, is administered prenatally to induce fetal lung maturation in women at risk of preterm delivery.…”

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confidence: 99%

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy

Samtani

Pyszczynski²,

DuBois³

et al. 2005

J Pharmacol Exp Ther

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Preterm birth produces neonatal respiratory distress syndrome, and dexamethasone (DEX) is administered maternally to induce fetal lung maturation in women at risk of preterm delivery. Antenatal DEX therapy is largely empirical, and administering multiple doses of DEX produces undesirable metabolic and developmental effects in the fetus. It is hypothesized that pharmacokinetic/pharmacodynamic (PK/PD) assessment of the maternal/fetal disposition and selected effects of corticosteroids will allow insight into optimal dosing methods. An optimal regimen was defined as a dosing schedule that would reproduce the endogenous prenatal steroid exposure and up-regulation of fetal lung maturational markers precociously. This report focuses on designing such a regimen from a PK standpoint in rats. The temporal profile of endogenous corticosterone in control rats was captured using a radioimmunoassay and showed that maternal and fetal corticosterone increased significantly during the last days of gestation. Six 1-mol kg Ϫ1 intramuscular DEX doses separated by 12-h intervals were administered maternally starting at gestational age 18, and PK was captured using a liquid chromatography-mass spectrometry assay. Unbound DEX exhibited a fetal to maternal concentration ratio of 0.55, had a free fraction of 0.2 in maternal and 0.4 in fetal plasma, and declined with a half-life of approximately 3 h. DEX PK and plasma protein binding were linear during the study, and DEX exposure caused severe adrenosuppression. These temporal steroid profiles in the fetal circulation will be used to drive the PD effects reported in a companion paper and an optimal steroid regimen will be proposed.Endogenous glucocorticoids play a pivotal role in programming the development of the fetus and preparing it for life outside the womb (Liggins, 1994). During most of its gestational life, the fetus is exposed to very low levels of corticosteroids. A surge of corticosteroids in late pregnancy turns on fetal lung surfactant production that is necessary for lung maturation. Preterm birth occurs in about 10% of pregnancies where the neonate does not experience the late gestational steroid surge. These prematurely born infants experience respiratory distress syndrome (RDS) and require mechanical lung ventilation, which itself can cause additional lung diseases. RDS is a major cause of infant mortality and is among the most common and costly medical problems afflicting prematurely born infants (National Institutes of Health Consensus Panel, 1995).Synthetic fluorinated corticosteroids exhibit transplacental passage when administered to pregnant women because of low affinity for maternal corticosteroid binding globulin (CBG) and poor breakdown by placental steroid metabolizing enzymes (Pugeat et al., 1981;Diederich et al., 1998). DEX, in the form of its soluble phosphate ester prodrug, is administered prenatally to induce fetal lung maturation in women at risk of preterm delivery. This exogenous steroid administration has been shown to reduce the incidence of ...

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“…The metabolism of the commonly used synthetic GC, Dex, differs from that of the endogenous GC, cortisol. Fluorine and methyl group substitutions in Dex limit its oxidoreduction by HSD1 and oxidation by HSD2 (15). Interestingly, HSD2 actively catalyzes the oxidoreduction of 11-dehydro-Dex (DH-Dex) to active Dex but does not oxidoreduce cortisone to cortisol (15).…”

mentioning

confidence: 99%

“…Fluorine and methyl group substitutions in Dex limit its oxidoreduction by HSD1 and oxidation by HSD2 (15). Interestingly, HSD2 actively catalyzes the oxidoreduction of 11-dehydro-Dex (DH-Dex) to active Dex but does not oxidoreduce cortisone to cortisol (15). Thus significant differences exist in the metabolism of cortisol vs. Dex by HSD2.…”

mentioning

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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Metabolism of Synthetic Corticosteroids by 11β-hydroxysteroid-Dehydrogenases in Man

Cited by 48 publications

References 29 publications

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy

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

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Metabolism of Synthetic Corticosteroids by 11β-hydroxysteroid-Dehydrogenases in Man

Cited by 48 publications

References 29 publications

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A2-dependent mechanism

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A2-dependent mechanism

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy

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

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Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism