scholarly journals 17β-Estradiol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes

2009 ◽  
Vol 202 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Noriko Tagawa ◽  
Ryosuke Yuda ◽  
Sayaka Kubota ◽  
Midori Wakabayashi ◽  
Yuko Yamaguchi ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Fat Depots ◽  
Mesenteric Fat ◽  
17Β Estradiol ◽  
Transcriptional Pathway ◽  
Insight Into ◽  
Full Activation

17β-Estradiol (E2) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E2 inhibited 11β-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E2 on 11β-HSD1 activity was observed within 5–10 min. Furthermore, acetylation or α-epimerization of 17-hydroxy group of E2 attenuated the inhibitory effect on 11β-HSD1. These results indicate that the inhibition of 11β-HSD1 by E2 depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11β-HSD1, was unaffected by E2. A kinetic study revealed that E2 acted as a non-competitive inhibitor of 11β-HSD1. The inhibitory effect of E2 on 11β-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E2 inhibits 11β-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.

scholarly journals Resveratrol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose microsomes

2013 ◽  
Vol 218 (3) ◽  
pp. 311-320 ◽  
Author(s):  
Noriko Tagawa ◽  
Sayaka Kubota ◽  
Ikuo Kato ◽  
Yoshiharu Kobayashi
Keyword(s):  
Adipose Tissue ◽  
Central Obesity ◽  
Hydroxysteroid Dehydrogenase ◽  
Competitive Inhibitor ◽  
Significant Inhibition ◽  
Epididymal Adipose Tissue ◽  
Receptor Blockers ◽  
Transcriptional Pathway ◽  
Dose Dependent

It has been suggested that resveratrol, a polyphenol in wine, can regulate adiposity because it decreases adipose deposition in mice and rats; however, the mechanism underlying this effect has not been fully clarified. In humans and rodents, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed in liver and adipose tissue. 11β-HSD1 converts inactive glucocorticoid into active glucocorticoid in adipocytes. Activated glucocorticoid plays an important role in the pathogenesis of central obesity. The objective of this study was to investigate the effects of resveratrol on 11β-HSD1 activity in rodent adipose tissue. 11β-HSD1 activity in microsomes from rat mesenteric adipose depots and 3T3-L1 adipocytes was determined in the presence of 11-dehydrocorticosterone with or without varying concentrations of resveratrol. Significant inhibition of 11β-HSD1 by resveratrol was observed in rat adipose microsomes and 3T3-L1 adipocytes within 10 min. Time- and dose-dependent effects were also observed. The 11β-HSD1 activity by resveratrol was also inhibited in rat epididymal adipose tissue, and this inhibition was not recovered by estrogen receptor blockers. The kinetic study revealed that resveratrol acted as a non-competitive inhibitor of 11β-HSD1.Kiand IC50values of resveratrol were 39.6 and 35.2 μM respectively. Further, resveratrol did not affect the activities of 11β-HSD2 and hexose-6-phosphate dehydrogenase. These results suggest that the most likely mechanism of 11β-HSD1 inhibition by resveratrol is via interaction between resveratrol and 11β-HSD1 enzyme, rather than via a transcriptional pathway. We demonstrated that the antiobesity effects of resveratrol may partially be attributed to the inhibition of 11β-HSD1 activity in adipocytes.

Overexpression of 17β-Hydroxysteroid Dehydrogenase Type 1 Increases the Exposure of Endometrial Cancer to 17β-Estradiol

2011 ◽  
pp. P2-217-P2-217
Author(s):  
Karlijn Cornel ◽  
Bert Delvoux ◽  
Laura Visconti ◽  
Roy Kruitwagen ◽  
Andrea Romano
Keyword(s):  
Endometrial Cancer ◽  
Hydroxysteroid Dehydrogenase ◽  
17Β Estradiol

scholarly journals Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis

2020 ◽  
Vol 71 (3) ◽  
pp. 249-264
Author(s):  
Bianka Edina Herman ◽  
János Gardi ◽  
János Julesz ◽  
Csaba Tömböly ◽  
Eszter Szánti-Pintér ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Inhibitory Effect ◽  
Ferrocene Derivatives ◽  
17Β Estradiol ◽  
Inhibitory Potential ◽  
Estrogen Biosynthesis

Abstract The potential inhibitory effect of diverse triazolyl-ferrocene steroids on key enzymes of the estrogen biosynthesis was investigated. Test compounds were synthesized via copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes using our efficient methodology published previously. Inhibition of human aromatase, steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activities was investigated with in vitro radiosubstrate incubations. Some of the test compounds were found to be potent inhibitors of the STS. A compound bearing ferrocenyl side chain on the C-2 displayed a reversible inhibition, whereas C-16 and C-17 derivatives displayed competitive irreversible binding mechanism toward the enzyme. 17α-Triazolyl-ferrocene derivatives of 17β-estradiol exerted outstanding inhibitory effect and experiments demonstrated a key role of the ferrocenyl moiety in the enhanced binding affinity. Submicromolar IC50 and Ki parameters enroll these compounds to the group of the most effective STS inhibitors published so far. STS inhibitory potential of the steroidal ferrocenes may lead to the development of novel compounds able to suppress in situ biosynthesis of 17β-estradiol in target tissues.

scholarly journals Retinoic acids promote the action of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 on the biosynthesis of 17beta-estradiol in placental cells

2002 ◽  
Vol 172 (1) ◽  
pp. 31-43 ◽  
Author(s):  
SJ Zhu ◽  
Y Li ◽  
H Li ◽  
YL Wang ◽  
ZJ Xiao ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Retinoic Acid Receptor ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effect ◽  
Retinoic Acids ◽  
Placental Cells ◽  
Choriocarcinoma Cells ◽  
Nadh Cytochrome ◽  
Reporter Gene Analysis

The biosynthesis of 17beta-estradiol (E(2)) in human placenta involves the actions of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 (17HSD1). Aromatase, an enzyme complex comprised of P450aromatase (P450arom) and NADH-cytochrome P450 reductase, converts androgens to estrogens, whereas 17HSD1 catalyzes the reduction of estrone to E(2). In the present study, the effects of retinoic acids (RAs) on P450arom and 17HSD1 expression in placental cells were investigated. Treatment with all-trans-RA (at-RA) or 9cis-RA increased E(2) production in JEG-3 choriocarcinoma cells and cytotrophoblast (CTB) cells isolated from normal early placentas. Meanwhile, the activity of aromatase and expression of P450arom mRNA were induced by at-RA in JEG-3 cells. Northern blot analysis showed that the effect on P450arom mRNA expression occurs in a dose- and time-dependent fashion. Similar to at-RA and 9cis-RA, Ro40-6055, the retinoic acid receptor alpha (RARalpha)-selective activator, increased the expression of P450arom and 17HSD1 mRNA in JEG-3 cells. On the other hand, Ro41-5253 (Ro41), the RARalpha-selective antagonist, blocked the stimulatory effect of RAs on P450arom expression. Surprisingly, Ro41 induced the activity and mRNA expression of 17HSD1 in JEG-3 cells, which is in contrast to the expected inhibitory effect and, moreover, remarkably potentiated the induction by at-RA and 9cis-RA. However, reporter gene analysis revealed that the influence of Ro41 on the transcription of the HSD17B1 gene, which encodes 17HSD1, is considerably milder in JEG-3 cells, and it only additively enhanced the effect of at-RA. Finally, it was found that at-RA and 9cis-RA increased the expression of P450arom and 17HSD1 mRNA in CTB cells, but to a lesser extent. The data suggest that RAs may play a role in promoting the biosynthesis of E(2 )in the placenta. In addition, Ro41 has divergent effects on gene expression in JEG-3 cells.

Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1

2017 ◽  
Vol 144 ◽  
pp. 149-161 ◽  
Author(s):  
Alexandre Trottier ◽  
René Maltais ◽  
Diana Ayan ◽  
Xavier Barbeau ◽  
Jenny Roy ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Hydroxysteroid Dehydrogenase ◽  
Insight Into

scholarly journals Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

2006 ◽  
Vol 190 (2) ◽  
pp. 363-371 ◽  
Author(s):  
Brenda Anguiano ◽  
Alejandra López ◽  
Guadalupe Delgado ◽  
Carlos Romero ◽  
Carmen Aceves
Keyword(s):  
Thyroid Hormones ◽  
Enzymatic Activity ◽  
Mrna Expression ◽  
Sex Hormones ◽  
Inhibitory Effect ◽  
Preferential Expression ◽  
Gold Thioglucose ◽  
17Β Estradiol

The aim of this study was to characterize the type of 5′-deiodinase activity in the prostate of pubescent rats (7–8 weeks), to establish its distribution in the lobes (ventral, dorsolateral, and anterior), and to analyze its modulation by prolactin (PRL), testosterone, dihydrotestosterone (DHT), and 17β-estradiol (E2). Our results showed that the enzymatic activity was highly susceptible to inhibition by 6-n-propyl-2-thiouracil and gold thioglucose, its preferential substrate was reverse tri-iodothyronine (rT3), it exhibited a low dithiothreitol requirement (5 mM), and the apparent Km and Vmax values for substrate (rT3) were approximately 0.25 μM and 9.0 pmol liberated/mg protein per hour, respectively. All these characteristics indicate the preferential expression of type 1 deiodinase (D1), which was corroborated by demonstrating the presence of D1 mRNA in prostate. D1 activity was detected in all lobes and was most abundant in the dorsolateral. Although we detected type 2 deiodinase (D2) mRNA expression, the D2 activity was almost undetectable. D1 activity was enhanced in animals with hyperthyroidism and hyperprolactinemia, in intact animals treated with finasteride (inhibitor of local DHT production), and in castrated animals with E2 replacement. In contrast, activity diminished in castrated animals with testosterone replacement. Our results suggest that thyroid hormones, PRL, and E2 exert a positive modulation on D1 activity, while testosterone and DHT exhibit an inhibitory effect. D1 activity may be associated with prostate maturation and/or function.

scholarly journals Inhibition of Type 1 17β-Hydroxysteroid Dehydrogenase Impairs the Synthesis of 17β-Estradiol in Endometriosis Lesions

2014 ◽  
Vol 99 (1) ◽  
pp. 276-284 ◽  
Author(s):  
Bert Delvoux ◽  
Thomas D'Hooghe ◽  
Cleophas Kyama ◽  
Pasi Koskimies ◽  
Rob J. J. Hermans ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
17Β Estradiol

scholarly journals Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

2007 ◽  
Vol 51 (8) ◽  
pp. 1397-1403 ◽  
Author(s):  
Daniela Espíndola-Antunes ◽  
Claudio E. Kater
Keyword(s):  
Adipose Tissue ◽  
Cushing’S Syndrome ◽  
Human Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Cushing's Syndrome ◽  
Intact Cells ◽  
Fat Depots ◽  
Cortisol Metabolism ◽  
The Metabolic Syndrome

Glucocorticoids have a major role in determining adipose tissue metabolism and distribution. 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADPH-dependent enzyme highly expressed in the liver and adipose tissue. In most intact cells and tissues it functions as a reductase (to convert inactive cortisone to active cortisol). It has been hypothesized that tissue-specific deregulation of cortisol metabolism may be involved in the complex pathophysiology of the metabolic syndrome (MS) and obesity. Transgenic mice overexpressing 11betaHSD1 in adipose tissue develop obesity with all features of the MS, whereas 11betaHSD1-knockout mice are protected from both. The bulk of evidences points to an overexpression and increased activity of 11betaHSD1 also in human adipose tissue. However, 11betaHSD1 seems to adjust local cortisol concentrations independently of its plasma levels. In Cushing's syndrome, 11betaHSD1 is downregulated and may not be responsible for the abdominal fat depots; it also undergoes downregulation in response to weight loss in human obesity. The nonselective 11betaHSD1 inhibitor carbenoxolone improves insulin sensitivity in humans, and selective inhibitors enhance insulin action in diabetic mice liver, thereby lowering blood glucose. Thus, 11betaHSD1 is now emerging as a modulator of energy partitioning and a promising pharmacological target to treat the MS and diabetes.

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