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  1. Article: The role of 11beta-hydroxysteroid dehydrogenases in the cardiovascular system.

    Krozowski, Zygmunt / Chai, Zhonglin

    Endocrine journal

    2003  Volume 50, Issue 5, Page(s) 485–489

    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/physiology ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/physiology ; Animals ; Cardiovascular Physiological Phenomena ; Glucocorticoids/metabolism ; Humans ; Hypertension/physiopathology ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Isoenzymes/physiology ; Obesity/metabolism ; Tissue Distribution
    Chemical Substances Glucocorticoids ; Isoenzymes ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146)
    Language English
    Publishing date 2003-10-21
    Publishing country Japan
    Document type Journal Article ; Review
    ZDB-ID 1151918-6
    ISSN 0918-8959
    ISSN 0918-8959
    DOI 10.1507/endocrj.50.485
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  2. Article: Arginine vasopressin stimulates 11beta-hydroxysteroid dehydrogenase type 2 expression in the mineralocorticosteroid target cells.

    Rubis, Blazej / Krozowski, Zygmunt / Trzeciak, Wieslaw H

    Molecular and cellular endocrinology

    2006  Volume 256, Issue 1-2, Page(s) 17–22

    Abstract: 11Beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) deficiency causes sodium retention and severe hypertension by allowing glucocorticoids access to the non-selective mineralocorticosteroid receptor. Understanding regulation of the HSD11B2 gene is ... ...

    Abstract 11Beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) deficiency causes sodium retention and severe hypertension by allowing glucocorticoids access to the non-selective mineralocorticosteroid receptor. Understanding regulation of the HSD11B2 gene is thus of fundamental importance in hypertension research. A number of studies have suggested that second messenger pathways may be important in this regard. In the present study we show that HSD11B2 expression in human renal epithelial P58 cells is regulated at the mRNA and protein level, and that protein kinases A (PKA) and C (PKC) are involved in this process. PKA stimulation resulted in almost two-fold increase while PKC activation in almost two-fold decrease in the HSD11B2 mRNA and protein level. Western blot analysis revealed a dimeric form of 11beta-HSD2 of about 80kDa. Arginine vasopressin (AVP), acting through the AVP2 receptor, as well as 11beta-HSD2 substrates, corticosterone and dexamethasone, up-regulate HSD11B2 expression, suggesting their role as possible factors affecting blood pressure. We show that the activators of the PKA pathway induce, while activators of PKC pathway repress the expression of HSD11B2 in human renal epithelial cells. AVP, acting via the PKA pathway, might be a physiological stimulator of the HSD11B2 expression. The 11beta-HSD2 substrates, both natural (corticosterone) and synthetic (dexamethasone), might protect the mineralocorticosteroid-target cells against cortisol excess.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism ; Animals ; Arginine Vasopressin/metabolism ; Cell Line ; Corticosterone/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Dexamethasone/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/physiology ; Gene Expression Regulation, Enzymologic ; Humans ; Kidney/cytology ; Mineralocorticoids/metabolism ; Protein Kinase C/metabolism ; Second Messenger Systems/physiology
    Chemical Substances Mineralocorticoids ; Arginine Vasopressin (113-79-1) ; Dexamethasone (7S5I7G3JQL) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Protein Kinase C (EC 2.7.11.13) ; Corticosterone (W980KJ009P)
    Language English
    Publishing date 2006-08-15
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2006.04.032
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  3. Article: Reduction of glucocorticoid receptor ligand binding by the 11-beta hydroxysteroid dehydrogenase type 2 inhibitor, Thiram.

    Garbrecht, Mark R / Krozowski, Zygmunt S / Snyder, Jeanne M / Schmidt, Thomas J

    Steroids

    2006  Volume 71, Issue 10, Page(s) 895–901

    Abstract: Endogenous and synthetic glucocorticoids (GCs), such as cortisol and dexamethasone (Dex), modulate airway inflammation, regulate the production of surfactant by lung epithelial cells, and influence fetal lung maturation. The 11-beta hydroxysteroid ... ...

    Abstract Endogenous and synthetic glucocorticoids (GCs), such as cortisol and dexamethasone (Dex), modulate airway inflammation, regulate the production of surfactant by lung epithelial cells, and influence fetal lung maturation. The 11-beta hydroxysteroid dehydrogenase type 2 (HSD2) enzyme catalyzes the oxidation of bioactive cortisol and Dex to their 11-keto metabolites. Thiram (tetramethylthiuram disulfide) specifically inhibits HSD2 activity by oxidizing cysteine residues located in the cofactor binding domain of the enzyme. During studies performed to define a potential role for HSD2 in modulating GC action in human lung epithelial cells, we observed that exposure of intact human lung epithelial cells (NCI-H441) to 50 microM Thiram significantly attenuated the down-stream effects of Dex (100 nM) on the expression of two GC-sensitive genes, pulmonary surfactant proteins A and B. This observation appeared to be inconsistent with simple inhibition of HSD2 activity. Although Thiram inhibited HSD2 oxidase activity in a dose-dependent manner without affecting HSD2 protein expression, Thiram also reduced specific binding of [3H]-Dex to the glucocorticoid receptor (GR). Pre-treatment of cells with 1 mM dithiothreitol (DTT), a thiol-reducing agent, completely blocked the inhibitory effect of Thiram on ligand binding. These results are suggestive that Thiram may alter the ligand-binding domain of the GR by oxidizing critical thiol-containing amino acid residues. Taken collectively, these data demonstrate that attenuated down-stream GC signaling, via decreased binding of ligand to the GR, is a novel cellular effect of Thiram exposure in human lung epithelial cells.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors ; Blotting, Northern ; Cell Line ; Dexamethasone/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Ligands ; Protein Binding ; Receptors, Glucocorticoid/metabolism ; Thiram/pharmacology
    Chemical Substances Enzyme Inhibitors ; Ligands ; Receptors, Glucocorticoid ; Thiram (0D771IS0FH) ; Dexamethasone (7S5I7G3JQL) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146)
    Language English
    Publishing date 2006-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80312-1
    ISSN 1878-5867 ; 0039-128X
    ISSN (online) 1878-5867
    ISSN 0039-128X
    DOI 10.1016/j.steroids.2006.06.001
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  4. Article: 11Beta-hydroxysteroid dehydrogenase type 2 and the regulation of surfactant protein A by dexamethasone metabolites.

    Garbrecht, Mark R / Schmidt, Thomas J / Krozowski, Zygmunt S / Snyder, Jeanne M

    American journal of physiology. Endocrinology and metabolism

    2006  Volume 290, Issue 4, Page(s) E653–60

    Abstract: Glucocorticoid (GC) metabolism by the 11beta-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- ...

    Abstract Glucocorticoid (GC) metabolism by the 11beta-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(-7) M). By contrast, HSD1 protein was undetectable. We also show that the Dex-mediated 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.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/biosynthesis ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/biosynthesis ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism ; Carbenoxolone/pharmacology ; Cell Line, Tumor ; Chenodeoxycholic Acid/pharmacology ; Dexamethasone/metabolism ; Dexamethasone/pharmacology ; Enzyme Inhibitors/pharmacology ; Glucocorticoids/metabolism ; Humans ; Infant, Newborn ; Lung/embryology ; Lung/enzymology ; Lung/metabolism ; Pulmonary Surfactant-Associated Protein A/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Up-Regulation/drug effects
    Chemical Substances Enzyme Inhibitors ; Glucocorticoids ; Pulmonary Surfactant-Associated Protein A ; Chenodeoxycholic Acid (0GEI24LG0J) ; Dexamethasone (7S5I7G3JQL) ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; HSD11B1 protein, human (EC 1.1.1.146) ; Carbenoxolone (MM6384NG73)
    Language English
    Publishing date 2006-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 603841-4
    ISSN 1522-1555 ; 0193-1849
    ISSN (online) 1522-1555
    ISSN 0193-1849
    DOI 10.1152/ajpendo.00396.2005
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  5. Article: Clinical relevance of airway 11beta-hydroxysteroid dehydrogenase type II enzyme in asthma.

    Orsida, Bernadette E / Krozowski, Zygmunt S / Walters, E Haydn

    American journal of respiratory and critical care medicine

    2002  Volume 165, Issue 7, Page(s) 1010–1014

    Abstract: 11beta-hydroxysteroid dehydrogenases (11beta-HSD) are responsible for the conversion of bioactive glucocorticoids to and from inactive metabolites. 11beta-HSD2 is generally considered a high-affinity inactivator of natural glucocorticoids, although its ... ...

    Abstract 11beta-hydroxysteroid dehydrogenases (11beta-HSD) are responsible for the conversion of bioactive glucocorticoids to and from inactive metabolites. 11beta-HSD2 is generally considered a high-affinity inactivator of natural glucocorticoids, although its activity with synthetic compounds in vivo is unknown. Inhaled corticosteroids (ICS) remain the primary antiinflammatory agents for treating asthma, but little is known about their metabolism in the lung. The aims of this study were to determine whether the 11beta-HSD2 enzyme can be localized to human airway tissue and whether differential expression of this enzyme relates to asthma severity and ICS needs. We studied airway biopsy specimens from 22 asthmatic subjects, in two groups: (1) a group not treated with ICS (n = 7); and (2) a group treated with ICS (range: 200 to 1,500 microg/d; n = 15). A control population consisted of nine nonasthmatic subjects. Immunostaining was done with an immunopurified antibody to human 11beta-HSD2. Immunoreactivity was generally localized to the endothelium of vessels in the lamina propria and to airway epithelium both in asthmatic patients and nonasthmatic controls. There was a statistically significant inverse relationship between the ICS dose required for effective treatment and the extent of epithelial 11beta-HSD2 staining (r = -0.44; p = 0.04). This is consistent with 11beta-HSD2 acting as an oxidoreductase that regenerates rather than inactivates ICS. This study suggests that glucocorticoid sensitivity in the lung is not determined by ICS breakdown, but may be related to 11beta-HSD2 sustaining the activation of synthetic glucocorticoids.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 2 ; Administration, Inhalation ; Administration, Topical ; Adult ; Aged ; Anti-Asthmatic Agents/administration & dosage ; Anti-Inflammatory Agents/administration & dosage ; Asthma/drug therapy ; Asthma/enzymology ; Asthma/physiopathology ; Beclomethasone/administration & dosage ; Bronchi/blood supply ; Bronchi/enzymology ; Endothelium, Vascular/enzymology ; Female ; Forced Expiratory Volume ; Glucocorticoids ; Humans ; Hydroxysteroid Dehydrogenases/metabolism ; Immunohistochemistry ; Male ; Middle Aged ; Respiratory Mucosa/enzymology
    Chemical Substances Anti-Asthmatic Agents ; Anti-Inflammatory Agents ; Glucocorticoids ; Hydroxysteroid Dehydrogenases (EC 1.1.-) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; HSD11B2 protein, human (EC 1.1.1.146) ; Beclomethasone (KGZ1SLC28Z)
    Language English
    Publishing date 2002-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 1073-449X ; 0003-0805
    ISSN (online) 1535-4970
    ISSN 1073-449X ; 0003-0805
    DOI 10.1164/ajrccm.165.7.2105003
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  6. Article: Altered activity of 11beta-hydroxysteroid dehydrogenase types 1 and 2 in skeletal muscle confers metabolic protection in subjects with type 2 diabetes.

    Jang, Christina / Obeyesekere, Varuni R / Dilley, Rodney J / Krozowski, Zygmunt / Inder, Warrick J / Alford, Frank P

    The Journal of clinical endocrinology and metabolism

    2007  Volume 92, Issue 8, Page(s) 3314–3320

    Abstract: Context: There is little information regarding the regulation of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes in skeletal muscle in the setting of type 2 diabetes.: Objective: Our objective was to investigate whether there is differential ...

    Abstract Context: There is little information regarding the regulation of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes in skeletal muscle in the setting of type 2 diabetes.
    Objective: Our objective was to investigate whether there is differential mRNA expression and enzyme activity of 11beta-HSD1 and 11beta-HSD2 in the skeletal muscle of diabetic subjects compared with controls at baseline and in response to dexamethasone.
    Design: Participants underwent muscle biopsy of vastus lateralis at baseline and after dexamethasone.
    Setting: The study took place at a university teaching hospital.
    Participants: Twelve subjects with type 2 diabetes and 12 age- and sex-matched controls participated.
    Intervention: Subjects were given oral dexamethasone, 4 mg/d for 4 d.
    Main outcome measures: We assessed 11beta-HSD1, 11beta-HSD2, and H6PDH mRNA levels by quantitative RT-PCR and enzyme activity by percent conversion of [(3)H]cortisone and [(3)H]cortisol, respectively.
    Results: At baseline, mRNA levels were similar in diabetic and control subjects for 11beta-HSD1, 11beta-HSD2, and H6PDH. 11beta-HSD1 activity was reduced in diabetic subjects (percent conversion of [(3)H]cortisone to [(3)H]cortisol was 11.4 +/- 2.5% vs. 18.5 +/- 2.2%; P = 0.041), and 11beta-HSD2 enzyme activity was higher in diabetic subjects (percent conversion of [(3)H]cortisone to [(3)H]cortisol was 17.2 +/- 2.6% vs. 9.2 +/- 1.3%; P = 0.012). After dexamethasone, 11beta-HSD1 mRNA increased in both groups (P < 0.001), whereas 11beta-HSD2 mRNA decreased (P = 0.002). 11beta-HSD1 activity increased in diabetic subjects (P = 0.021) but not in controls, whereas 11beta-HSD2 activity did not change in either group. At baseline, there was a significant negative correlation between 11beta-HSD1 and 11beta-HSD2 enzyme activity (r = -0.463; P = 0.026).
    Conclusions: The activities of skeletal muscle 11beta-HSD1 and 11beta-HSD2 are altered in diabetes, which together may reduce intracellular cortisol generation, potentially conferring metabolic protection.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism ; Blood Glucose/metabolism ; Cortisone/metabolism ; Dexamethasone/pharmacology ; Diabetes Mellitus, Type 2/enzymology ; Diabetes Mellitus, Type 2/metabolism ; Female ; Humans ; Hydrocortisone/metabolism ; Immunohistochemistry ; Male ; Middle Aged ; Muscle, Skeletal/enzymology ; RNA, Messenger/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction
    Chemical Substances Blood Glucose ; RNA, Messenger ; Dexamethasone (7S5I7G3JQL) ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; Cortisone (V27W9254FZ) ; Hydrocortisone (WI4X0X7BPJ)
    Language English
    Publishing date 2007-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/jc.2006-2729
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  7. Article: Expression of sterol 27-hydroxylase (CYP27A1) enhances cholesterol efflux.

    Escher, Genevieve / Krozowski, Zygmunt / Croft, Kevin D / Sviridov, Dmitri

    The Journal of biological chemistry

    2003  Volume 278, Issue 13, Page(s) 11015–11019

    Abstract: Cholesterol efflux from CHOP cells transfected with sterol 27-hydroxylase (CYP27A1) was compared with non-transfected and mock-transfected cells. Transfection caused expression of CYP27A1, formation of 27-hydroxycholesterol, and inhibition of cholesterol ...

    Abstract Cholesterol efflux from CHOP cells transfected with sterol 27-hydroxylase (CYP27A1) was compared with non-transfected and mock-transfected cells. Transfection caused expression of CYP27A1, formation of 27-hydroxycholesterol, and inhibition of cholesterol biosynthesis. Transfection enhanced cholesterol efflux to apolipoprotein A-I or human plasma by 2-3-fold but did not affect the efflux in the absence of acceptor. The analysis of released sterols revealed that 27-hydroxycholesterol represented only a small proportion of sterols, most of which was non-oxidized cholesterol. Time course and dose dependence studies showed that expression of CYP27A1 in CHOP cells mostly affected the efflux of the "fast" cholesterol pool, and relatively more cholesterol was released with low concentrations of an acceptor. Preincubation of non-transfected cells with exogenous 27-hydroxycholesterol (10(-9) and 10(-7) m) led to the stimulation of cholesterol efflux by 24-60%. Expression of CYP27A1 in CHOP cells did not affect ABCA1 expression and abundance of ABCA1 protein. Thus, introduction of CYP27A1 into cells stimulates cholesterol efflux and therefore may increase protection against atherosclerosis.
    MeSH term(s) Animals ; Biological Transport ; CHO Cells ; Cholestanetriol 26-Monooxygenase ; Cholesterol/metabolism ; Chromatography, Thin Layer ; Cricetinae ; DNA Primers ; Humans ; Steroid Hydroxylases/metabolism
    Chemical Substances DNA Primers ; Cholesterol (97C5T2UQ7J) ; Steroid Hydroxylases (EC 1.14.-) ; CYP27A1 protein, human (EC 1.14.15.15) ; Cholestanetriol 26-Monooxygenase (EC 1.14.15.15)
    Language English
    Publishing date 2003-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M212780200
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  8. Article: Localization of 11beta-hydroxysteroid dehydrogenase types 1 and 2 in the male reproductive tract.

    Waddell, Brendan J / Hisheh, Susan / Krozowski, Zygmunt S / Burton, Peter J

    Endocrinology

    2003  Volume 144, Issue 7, Page(s) 3101–3106

    Abstract: The action of glucocorticoids in target tissues is dependent on the local expression of glucocorticoid receptors and two 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes, 11beta-HSD1 and 11beta-HSD2, which interconvert active and inactive ... ...

    Abstract The action of glucocorticoids in target tissues is dependent on the local expression of glucocorticoid receptors and two 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes, 11beta-HSD1 and 11beta-HSD2, which interconvert active and inactive glucocorticoids. This study examined expression of the 11beta-HSD enzymes in the male reproductive tract of the adult rat. 11beta-HSD1 was immunolocalized to the apical region of principal epithelial cells of the caput epididymis, with the less numerous clear cells devoid of signal. Epididymal 11beta-HSD1 expression was confirmed by Western blot analysis, with immunoreactive species identified at 34 kDa (the expected size for 11beta-HSD1) and at approximately 48 kDa. 11beta-HSD bioactivity was readily detectable in the epididymis, with 11-oxoreductase activity clearly the favored reaction (as observed in liver), consistent with 11beta-HSD1 expression. The epithelium of the vas deferens, seminal vesicle, and penile urethra were also immunopositive for 11beta-HSD1, as were smooth muscle cells of the vas deferens and penile blood vessels. 11beta-HSD2 was also immunolocalized to the epididymal epithelium, but its distribution was complementary to that of 11beta-HSD1 (i.e. clear cells showing intense 11beta-HSD2 staining but principal cells devoid of signal). 11beta-HSD2 was also present in the corpora cavernosa of the penis but not in other tissues. In conclusion, the differential expression of 11beta-HSD1 and 11beta-HSD2 throughout the male reproductive tract suggests that these enzymes locally modulate glucocorticoid and mineralocorticoid actions, particularly in the epididymis and penile vasculature.
    MeSH term(s) 11-beta-Hydroxysteroid Dehydrogenase Type 2 ; 11-beta-Hydroxysteroid Dehydrogenases ; Animals ; Blotting, Western ; Epididymis/enzymology ; Hydroxysteroid Dehydrogenases/analysis ; Immunohistochemistry ; Male ; Penis/blood supply ; Penis/enzymology ; Rats ; Rats, Wistar ; Seminal Vesicles/enzymology ; Seminiferous Epithelium/enzymology ; Urethra/enzymology ; Vas Deferens/enzymology
    Chemical Substances Hydroxysteroid Dehydrogenases (EC 1.1.-) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; 11-beta-Hydroxysteroid Dehydrogenases (EC 1.1.1.146)
    Language English
    Publishing date 2003-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2003-0082
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  9. Article ; Online: Role of CYP27A1 in progesterone metabolism in vitro and in vivo.

    Escher, Geneviève / Vögeli, Isabelle / Escher, Robert / Tuckey, Robert C / Erickson, Sandra / Krozowski, Zygmunt / Frey, Felix J

    American journal of physiology. Endocrinology and metabolism

    2009  Volume 297, Issue 4, Page(s) E949–55

    Abstract: In the kidney, progesterone is inactivated to 20alpha-dihydro-progesterone (20alpha-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20alpha-hydroxysteroid activity using ... ...

    Abstract In the kidney, progesterone is inactivated to 20alpha-dihydro-progesterone (20alpha-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20alpha-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20alpha-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone to 20alpha-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20alpha-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20alpha-DH-progesterone increased, and the progesterone-to-20alpha-DH-progesterone ratio decreased threefold (P < 0.001). Thus CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20alpha-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.
    MeSH term(s) Adrenodoxin/biosynthesis ; Animals ; Biotransformation ; Blotting, Western ; Cell Line ; Cholestanetriol 26-Monooxygenase/genetics ; Cholestanetriol 26-Monooxygenase/metabolism ; Cloning, Molecular ; Electron Transport ; Female ; Ferredoxin-NADP Reductase/biosynthesis ; Gas Chromatography-Mass Spectrometry ; Gene Library ; Humans ; Hydroxycholesterols/metabolism ; Kidney/metabolism ; Male ; Mice ; Mice, Knockout ; Progesterone/blood ; Progesterone/metabolism ; Transfection
    Chemical Substances Hydroxycholesterols ; Adrenodoxin (12687-22-8) ; Progesterone (4G7DS2Q64Y) ; 27-hydroxycholesterol (6T2NA6P5SQ) ; CYP27A1 protein, human (EC 1.14.15.15) ; Cholestanetriol 26-Monooxygenase (EC 1.14.15.15) ; Cyp27a1 protein, mouse (EC 1.14.15.15) ; Ferredoxin-NADP Reductase (EC 1.18.1.2)
    Language English
    Publishing date 2009-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603841-4
    ISSN 1522-1555 ; 0193-1849
    ISSN (online) 1522-1555
    ISSN 0193-1849
    DOI 10.1152/ajpendo.00298.2009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Expression of caveolin-1 enhances cholesterol efflux in hepatic cells.

    Fu, Ying / Hoang, Anh / Escher, Genevieve / Parton, Robert G / Krozowski, Zygmunt / Sviridov, Dmitri

    The Journal of biological chemistry

    2004  Volume 279, Issue 14, Page(s) 14140–14146

    Abstract: HepG2 cells were stably transfected with human caveolin-1 (HepG2/cav cells). Transfection resulted in expression of caveolin-1 mRNA, a high abundance of caveolin-1 protein, and the formation of caveolae on the plasma membrane. Cholesterol efflux from ... ...

    Abstract HepG2 cells were stably transfected with human caveolin-1 (HepG2/cav cells). Transfection resulted in expression of caveolin-1 mRNA, a high abundance of caveolin-1 protein, and the formation of caveolae on the plasma membrane. Cholesterol efflux from HepG2/cav cells was 280 and 45% higher than that from parent HepG2 cells when human plasma and human apoA-I, respectively, were used as acceptors. The difference in efflux was eliminated by treatment of cells with progesterone. There was no difference in cholesterol efflux to cyclodextrin. Cholesterol efflux from plasma membrane vesicles was similar for the two cell types. Transfection led to a 40% increase in the amount of plasma membrane cholesterol in cholesterol-rich domains (caveolae and/or rafts) and a 67% increase in the rate of cholesterol trafficking from intracellular compartments to these domains. Cholesterol biosynthesis in HepG2/cav cells was increased by 2-fold, and cholesterol esterification was reduced by 50% compared with parent HepG2 cells. The proliferation rate of transfected cells was significantly lower than that of non-transfected cells. Transfection did not affect expression of ABCA1 or the abundance of ABCA1 protein, but decreased secretion of apoA-I. We conclude that overexpression of caveolin-1 in hepatic cells stimulates cholesterol efflux by enhancing transfer of cholesterol to cholesterol-rich domains in the plasma membrane.
    MeSH term(s) ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/genetics ; Carcinoma, Hepatocellular ; Caveolin 1 ; Caveolins/genetics ; Caveolins/metabolism ; Cell Division ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cholesterol/biosynthesis ; Cholesterol/metabolism ; Esterification ; Gene Expression ; Humans ; Liver/cytology ; Transfection
    Chemical Substances ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; CAV1 protein, human ; Caveolin 1 ; Caveolins ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2004-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M311061200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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