Numerous chemicals in the environment have the ability to interact with the endocrine system. These compounds are called endocrine disruptors (EDs). Exposure to EDs represents one of the hypotheses for decreasing fertility, the increased risk of numerous cancers and obesity, metabolic syndrome and type 2 diabetes. There are various mechanisms of ED action, one of which is their interference in the action of 11β-hydroxysteroid dehydrogenase (11βHSD) that maintains a balance between active and inactive glucocorticoids on the intracellular level. This enzyme has two isoforms and is expressed in various tissues. Inhibition of 11βHSD in various tissues can have different consequences. In the case of EDs, the results of exposure are mainly adverse; on the other hand pharmaceutically developed inhibitors of 11βHSD type 1 are evaluated as an option for treating metabolic syndrome, as well as related diseases and depressive disorders. This review focuses on the effects of 11βHSD inhibitors in the testis, colon, adipose tissue, kidney, brain and placenta.

• Klíčová slova
• 11β-hydroxysteroid dehydrogenase, Adipose tissue, Brain, Colon, Endocrine disruptor, Inhibitor, Placenta, Testis,
• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 antagonisté a inhibitory   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 antagonisté a inhibitory   metabolismus   MeSH
• diabetes mellitus chemicky indukované   enzymologie   patologie   MeSH
• endokrinní disruptory farmakologie   MeSH
• glukokortikoidy metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• kolon účinky léků   enzymologie   MeSH
• lidé MeSH
• metabolický syndrom chemicky indukované   enzymologie   patologie   MeSH
• mozek účinky léků   enzymologie   MeSH
• nádory chemicky indukované   enzymologie   patologie   MeSH
• obezita chemicky indukované   enzymologie   patologie   MeSH
• orgánová specificita MeSH
• placenta účinky léků   enzymologie   MeSH
• těhotenství MeSH
• testis účinky léků   enzymologie   MeSH
• tuková tkáň účinky léků   enzymologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• endokrinní disruptory MeSH
• glukokortikoidy MeSH
• inhibitory enzymů MeSH

Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is the key enzyme which protects the fetus from overexposure to glucocorticoids (GCs) by their oxidation into inactive derivates. Several recent studies suggest that 11 beta-HSD2 expression is subjected to regulation by antenatal steroid therapy. In our study we investigated the effect of two commonly used synthetic steroids, dexamethasone (DXM) and betamethasone (BTM), on the expression and function of 11 beta-HSD2 in the rat placenta. Pregnant rats were pretreated with low (0.2mg/kg) or high (5mg/kg and 11.5mg/kg for DXM and BTM, respectively) i.m. doses of GCs. 11 beta-HSD2 expression was investigated using real-time RT-PCR and Western blotting; conversion capacity of 11 beta-HSD2 was assessed by dual perfusion of the rat placenta. Significant increase in placental 11 beta-HSD2 mRNA expression was found in rats treated with DXM, however, this alteration was not observed on protein level. BTM had no effect on either mRNA or protein levels of 11 beta-HSD2. Functional studies revealed that both GCs significantly reduced the metabolism of corticosterone by the placenta. Our data indicate that placental barrier function mediated by 11 beta-HSD2 might be considerably impaired by the antenatal therapy with DXM and BTM. In addition, the discrepancy between expressional and functional studies suggests that sole analysis of expressional changes of 11 beta-HSD2 at mRNA and/or protein levels cannot convincingly predict the role of GC treatment on 11 beta-HSD2 function in the placental barrier.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• betamethason aplikace a dávkování   metabolismus   toxicita   MeSH
• dexamethason aplikace a dávkování   metabolismus   toxicita   MeSH
• glukokortikoidy aplikace a dávkování   metabolismus   toxicita   MeSH
• injekce intramuskulární MeSH
• krysa rodu Rattus MeSH
• messenger RNA metabolismus   MeSH
• perfuze MeSH
• placenta účinky léků   enzymologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• porodní hmotnost účinky léků   MeSH
• potkani Wistar MeSH
• regulace genové exprese účinky léků   MeSH
• těhotenství MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• betamethason MeSH
• dexamethason MeSH
• glukokortikoidy MeSH
• messenger RNA MeSH

OBJECTIVE: The objective of this study was to investigate the role of 11beta-hydroxysteroid dehydrogenases (11HSD1 and 11HSD2) in determining the fetal concentration of glucocorticoids. METHODS: The expression patterns for mRNA abundance, protein level, and enzyme activities of placental and fetal 11HSD1 and 11HSD2 were assessed from embryonic day 13 (E13) to day 21 (E21; term E22). The transplacental passage of maternal corticosterone and its contribution to fetal glucocorticoids was also studied. RESULTS: Placental 11HSD1 mRNA decreased between days E13 and E14 and then remained at much lower values up to E21. Similarly, NADP+-dependent 11beta-oxidation and 11-reduction were lower in late gestation. In contrast, placental 11HSD2 mRNA and protein decreased between E13 and E21. Dithiothreitol increased the activity of 11HSD2 and the output of 11-dehydrocorticosterone into fetal circulation.The fetal activity of 11HSD1 increased and 11HSD2 decreased between E16 and E21. CONCLUSIONS: The final third of gestation is accompanied by reciprocal changes in placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2 not only at the level of transcription but also at a posttranslational level.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• placenta enzymologie   metabolismus   MeSH
• plod MeSH
• potkani Wistar MeSH
• techniky in vitro MeSH
• těhotenství u zvířat metabolismus   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• kortikosteron MeSH

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-alpha, and IL-1beta mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-alpha, and IL-1beta, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-alpha, and IL-1beta in inflamed tissue.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• antagonisté hormonů farmakologie   MeSH
• budesonid farmakologie   MeSH
• cyklooxygenasa 2 genetika   metabolismus   MeSH
• glukokortikoidy antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• interleukin-1beta genetika   metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• kolitida chemicky indukované   metabolismus   MeSH
• kolon účinky léků   enzymologie   metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA metabolismus   MeSH
• mifepriston farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• mucin 2 MeSH
• muciny genetika   metabolismus   MeSH
• peroxidasa metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• TNF-alfa genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• antagonisté hormonů MeSH
• budesonid MeSH
• cyklooxygenasa 2 MeSH
• glukokortikoidy MeSH
• interleukin-1beta MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• mifepriston MeSH
• Muc2 protein, rat MeSH Prohlížeč
• mucin 2 MeSH
• muciny MeSH
• peroxidasa MeSH
• Ptgs2 protein, rat MeSH Prohlížeč
• TNF-alfa MeSH

NAD(+)-dependent 11beta-hydroxysteroid dehydrogenase (11HSD2) converts glucocorticoids to 11-oxo derivatives and thus decreases their local concentration and prevents them from activating corticosteroid receptors. In this paper we report the partial cloning, characterization and tissue distribution of chicken 11HSD2. A cDNA of 991bp was cloned from kidney mRNA by reverse transcription and polymerase chain reaction. At the amino acid level, the sequence of PCR product had 56-59% homology with mammalian and 46-48% with fish 11HSD2. The consensus sequences of the short-chain dehydrogenase/reductase superfamily such as the catalytic activity motif Tyr-X-X-X-Lys and cosubstrate-binding motif Gly-X-X-X-Gly-X-Gly, were found in the cloned cDNA. Analysis of the tissue expression of chicken 11HSD2 mRNA and NAD(+)-dependent 11beta-oxidase activity showed a similar tissue distribution pattern in the majority of tissues. High levels of expression and activity were found in kidney, small intestine, colon and oviduct; low in ovary and almost zero in brain, liver and testis.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• klonování DNA MeSH
• komplementární DNA metabolismus   MeSH
• kur domácí genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• molekulární sekvence - údaje MeSH
• ptačí proteiny genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sekvenční seřazení MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• komplementární DNA MeSH
• messenger RNA MeSH
• ptačí proteiny MeSH

Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• biologický transport MeSH
• karbenoxolon farmakologie   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• perfuze MeSH
• placenta enzymologie   metabolismus   fyziologie   MeSH
• techniky in vitro MeSH
• těhotenství metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• karbenoxolon MeSH
• kortikosteron MeSH

Glucocorticoid hormones have been reported to operate as regulators of cell proliferation and differentiation and to inhibit growth of several colon tumors and adenocarcinoma cell lines. The glucocorticoid action is regulated, in part, at the pre-receptor level through the expression of isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD1, 11betaHSD2) which are responsible for the interconversion of hormonally active cortisol to cortisone. Since both of these isoforms are expressed in the mammalian colon, we examined whether 11betaHSD1 and 11betaHSD2 are expressed in human colorectal cancer and whether their expression differs between neoplastic and autologous non-neoplastic tissue. We provide evidence that both isoforms of 11betaHSD are expressed in the colon adenocarcinoma, but their expression is not identical in neoplastic and non-neoplastic tissue. There is a significant decrease of 11betaHSD2 mRNA abundance and enzyme activity in neoplastic tissue. In contrast, 11betaHSD1 activity and mRNA abundance are increased in some but not all tumor samples. The results demonstrate that (1) neoplastic transformation is associated with decreasing steady-state levels of 11betaHSD2 mRNA and enzyme activity and in some cases also with increasing expression of 11betaHSD1, and (2) colorectal tumor cells have a decreased capability of autocrine inactivation of glucocorticoids.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• adenokarcinom enzymologie   genetika   patologie   MeSH
• hydrokortison metabolismus   MeSH
• izoenzymy genetika   MeSH
• kolorektální nádory enzymologie   genetika   patologie   MeSH
• kortison metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• hydrokortison MeSH
• izoenzymy MeSH
• kortison MeSH
• messenger RNA MeSH

BACKGROUND: Pro-inflammatory processes are counteracted by anti-inflammatory factors such as glucocorticoids. The response of target cells to glucocorticoids depends on several factors including prereceptor modulation of glucocorticoid signals via local glucocorticoid metabolism. This is determined by two isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD); 11betaHSD1 operates in vivo as a reductase converting inactive 11-oxo glucocorticoids to active glucocorticoids cortisol or corticosterone, whereas 11betaHSD2 catalyses oxidation of active glucocorticoids to their inactive 11-oxo derivatives. The aim of this study was to investigate the changes in local metabolism of glucocorticoids and in the expression of 11betaHSD1 and 11betaHSD2 mRNA during colonic inflammation. METHODS: Acute colitis was induced by intracolonic administration of 2,4,6-trinitrobenzenesulphonic acid (TNBS) or by drinking a dextran sodium sulphate (DSS) solution. Metabolism of glucocorticoids was measured in tissue fragments in vitro and 11betaHSD1 and 11betaHSD2 mRNA abundance was quantified using real-time RT-PCR one week after administration of TNBS and 10 days after drinking the DSS solution. RESULTS: In both models of inflammatory bowel disease we observed down-regulation of corticosterone oxidation to 11-dehydrocorticosterone by 64% (TNBS) and 53% (DSS) and reciprocal stimulation of reduction of 11-dehydrocorticosterone to corticosterone by 83% and 54%, respectively. A similar pattern was observed at the level of mRNA; 11betaHSD1 mRNA was significantly higher (TNBS: increase by 660%; DSS: increase by 760%) and 11betaHSD2 mRNA lower (TNBS: decrease by 85%; DSS: decrease by 60%) during inflammation. CONCLUSIONS: Colitis induces local glucocorticoid activation from 11-oxo steroids and decreases glucocorticoid inactivation; i.e. inflammation increases local tissue ratio of active and inactive glucocorticoids. The results indicate that the changes in local metabolism of glucocorticoids could contribute to the control of an overshoot of inflammation processes in the colon.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• Crohnova nemoc chemicky indukované   enzymologie   MeSH
• kortikosteron analogy a deriváty   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA genetika   MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar MeSH
• síran dextranu MeSH
• ulcerózní kolitida chemicky indukované   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• 11-dehydrocorticosterone MeSH Prohlížeč
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• síran dextranu MeSH