Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid metabolism was investigated in cultured human B-lymphoblastoid cells (B-LCL), and peripheral blood T and B cells. Gene expression was examined by reverse-transcription polymerase chain reaction amplification (RT-PCR). Appropriate sized transcripts were detected in both cultured and fresh peripheral lymphocytes for CYP11A, CYP17, HSD11L (11beta-hydroxysteroid dehydrogenase I), HSD17B1 (17beta-hydroxysteroid dehydrogenase type I) and SRD5A1 (5alpha-reductase I). B-LCL, but not T and B cells, expressed CYP11B. There was minimal expression of HSD3B1 and HSD3B2 (3beta-hydroxysteroid dehydrogenase I and II) in B-LCL and T cells. Transcripts for CYP19 and HSD11K were not detected. Corresponding enzymatic activity was detectable only for 17-hydroxysteroid dehydrogenase and 5alpha-reductase, respectively producing testosterone and 5alpha-dihydrotestosterone. Steroid identities were confirmed by gas chromatography/mass spectrometry (GC/MS). One metabolite thought to be deoxycorticosterone was identified by GC/MS as 6alpha-hydroxypregnanolone. It was concluded that sex hormone metabolism, including androgen synthesis, occurs in lymphocytes, and may modulate immune response.
Mol Cell Endocrinol 1998 Mar 16
PMID:Prominent sex steroid metabolism in human lymphocytes. 968 15

This study evaluated the levels and the enzymatic characteristics of 11beta-hydroxysteroid dehydrogenase activity (11beta-HSD) of chorionic villi isolated from first trimester human placenta. The results demonstrated a predominant expression of the NAD-dependent dehydrogenase isoform (11beta-HSD2) over the NADP-dependent oxoreductase (11beta-HSD1). Thus, in tissue homogenates exogenous NAD increased the conversion of corticosterone to 11-dehydrocorticosterone of about 14-fold while NADP was ineffective. There was no conversion of 11-dehydrocorticosterone to corticosterone either with NADH or NADPH demonstrating the lack of reductase activity. In keeping with these results, RT-PCR analysis indicated a mRNA for 11beta-HSD2 in villous tissue while 11beta-HSD1 mRNA levels were undetectable. In addition, immunohistochemical staining localized the 11beta-HSD2 protein to syncytiotrophoblasts and cell columns of the chorionic villi. These results suggest roles for the trophoblast-associated 11beta-HSD2 oxidative activity in modulating the exposure of the embryo to active glucocorticoids in the early gestation and in regulating trophoblasts invasion of the uterine wall.
Mol Cell Endocrinol 1998 Jun 25
PMID:11Beta-hydroxysteroid dehydrogenase expression in first trimester human trophoblasts. 972 80

Physiological responses due to steroid hormones and retinoids are regulated by their cognate receptors and dehydrogenases. The origins of either regulatory mechanism are not fully understood. Here we examine the origins of the human 11beta-hydroxysteroid dehydrogenase-type 2, which regulates access of glucocorticoids to cells, and 17beta-hydroxysteroid dehydrogenase-type 2, which regulates access of androgens and estrogens to cells. Sequence comparisons trace their ancestry to homologs in Caenorhabditis elegans. These C. elegans proteins most closely resemble mammalian all-trans and 11-cis-retinol dehydrogenases. The similarity is sufficient -37% to 43% identity to suggest that one or more of the C. elegans homologs metabolizes a retinoid. Receptors for retinoids, but not for androgens, estrogens or glucocorticoids have been identified in C. elegans, suggesting that retinoid-mediated gene transcription is more ancient than that for adrenal and sex steroids. We propose that the hydroxysteroid dehydrogenase-type 2 mechanism for regulating the androgen, estrogen and glucocorticoid concentrations in mammals descended from that for regulating retinoid concentrations. Interestingly, E. coli contains a protein with strong sequence similarity to mammalian retinol dehydrogenases. Sequence comparisons and phylogenetic analysis indicate that the E. coli protein may be an example of horizontal transfer from a eukaryote ancestor.
J Steroid Biochem Mol Biol 1998 Sep
PMID:Evolution of mammalian 11beta- and 17beta-hydroxysteroid dehydrogenases-type 2 and retinol dehydrogenases from ancestors in Caenorhabditis elegans and evidence for horizontal transfer of a eukaryote dehydrogenase to E. coli. 974 41

Mineralocorticoids have been implicated in promoting fibrous tissue formation in various organs. In the present study, we sought to address the potential contribution of mineralocorticoids to fibrous tissue formation using a skin pouch model which has proved valuable for the analysis of inflammatory and wound healing responses. Skin pouches were induced in rats by administration of a phorbol ester, croton oil (0.5 ml of a 1% solution). After 2 weeks, rats were killed and intact pouch tissue collected. Pouch weights of control and aldosterone-treated (0.75 microg/h via osmotic minipump) rats were similar (3.33 +/- 0.44 g vs. 3.70 +/- 0.28 g respectively). However, pouch weights were reduced by more than 50% in spironolactone-treated (25 mg/day powdered in food) animals (1.62 +/- 0.22 g and 1.27 +/- 0.23 g respectively in aldosterone and spironolactone alone groups). To ascertain the effects of different treatments on collagen accumulation, hydroxyproline concentration was measured. Compared with controls, hydroxyproline concentration was significantly reduced following spironolactone treatment (17.1 +/- 0.08 vs. 7.5 +/- 2.0 microg/mg dry wt, respectively, p < 0.01). This response to spironolactone was negated by coadministration of aldosterone (hydroxyproline concentration was 18.6 +/- 2.1 microg/mg dry wt). Following bilateral adrenalectomy, spironolactone reduced pouch weight and hydroxyproline concentration, which was not the case for adrenalectomy alone. Two week aldosterone administration in uninephrectomized rats on high salt diet was deemed ineffective in modulating pouch development (pouch wet wts were 3.48 +/- 0.4 g vs. 3.00 +/- 0.19 g in controls and aldosterone-treated rats, respectively). Mineralocorticoid receptor expression in pouch tissue was demonstrated by RT/PCR. Furthermore, NADP+-dependent 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activity was detected in pouch tissue, together with lower levels of NAD+-dependent 11beta-HSD2. Spironolactone (p < 0.05) significantly reduced 11beta-HSD1 activity compared with controls. Thus, fibrous tissue possesses requisite components of MC action, and antagonism of mineralocorticoid receptors by spironolactone attenuates its formation. Pouch formation is under the influence of circulating MC and, we would like to propose, is also mediated through corticosteroids generated de novo at the site of tissue repair.
Mol Cell Biochem 1998 Dec
PMID:Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation. 987 53

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.
J Steroid Biochem Mol Biol 1998 Nov
PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer. 988 91

The 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD) interconvert cortisol and cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. Two distantly related congeners have been isolated and conserved domains identified by multiple alignment and hydrophobic cluster analysis. 11Beta-HSD1 in the liver acts mainly as an oxoreductase maintaining circulating glucocorticoid levels. Gene deletion studies suggest it plays an important role in providing elevated local concentrations of hormone. In contrast, 11beta-HSD2 inactivates glucocorticoids and is pivotal in the distal tubule where it protects the mineralocorticoid receptor from occupation, thus endowing specificity on a non-selective receptor. Mutations in 11beta-HSD2 result in sodium retention and severe hypertension, account for the syndrome of apparent mineralocorticoid excess and may be responsible for other forms of hypertension. 11Beta-HSD2 is also present in the placenta where it protects the fetus from high circulating levels of maternal glucocorticoids. Attenuated placental 11beta-HSD2 activity has recently been shown to be associated with intrauterine growth retardation. 11Beta-HSD2 may also play important roles in pulmonary physiology and breast cancer. This review focuses on recent developments.
Mol Cell Endocrinol 1999 May 25
PMID:The 11beta-hydroxysteroid dehydrogenases: functions and physiological effects. 1041 26

The type 2 isozyme of 11beta-hydroxysteroid dehydrogenase inactivates cortisol to cortisone and enables aldosterone to bind to the MR. Congenital deficiency of the enzyme results in cortisol-mediated mineralocorticoid excess and arises because of inactivating mutations in the HSD11B2 gene. Inhibition of the enzyme following licorice or carbenoxolone ingestion results in a similar, though milder phenotype and the enzyme is overwhelmed in ectopic ACTH syndrome. Loss of 11beta-HSD2 expression may be important in sodium balance and blood pressure control in some patients with renal disease. Finally, while some studies demonstrate impaired 11beta-HSD activity in broader populations of patients with hypertension, further studies are required to clarify the role of 11beta-HSD2 in 'essential' hypertension.
J Steroid Biochem Mol Biol
PMID:Cortisol as a mineralocorticoid in human disease. 1041 18

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
J Steroid Biochem Mol Biol
PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

11beta-hydroxysteroid dehydrogenase (11betaHSD) reversibly converts hydrocortisone, the predominant active endogenous glucocorticoid in humans, to its inactive metabolite cortisone by oxidizing the 11-hydroxy group to an 11-keto group. Because this enzyme is highly expressed in human bronchial epithelial cells, we hypothesized that it regulates epithelial responses to glucocorticoids by reducing levels of hydrocortisone available to bind to the glucocorticoid receptor. Primary human bronchial epithelial cells (PBECs) were isolated from seven autopsy specimens and cultured in F12/Dulbecco's modified Eagle's medium with 5% fetal bovine serum until approximately 80% confluent. Cells were preincubated with 10(-9) M to 10(-5) M hydrocortisone for 24 h in the presence or absence of 10(-6) M of the 11betaHSD inhibitor glycyrrhetinic acid, after which the cells were stimulated with 5 ng/ml interleukin-1beta for 24 h. Granulocyte macrophage colony-stimulating factor (GM-CSF) levels were quantitated in the resulting supernatants by enzyme-linked immunosorbent assay. Hydrocortisone inhibited GM-CSF release in stimulated PBEC with a concentration that produces 50% inhibition of maximum effect (IC(1/2)max) of 5.0 x 10(-8) M. In the presence of glycyrrhetinic acid, the potency of hydrocortisone was increased approximately 33-fold (IC(1/2)max with glycyrrhetinic acid, 1.5 x 10(-9) M). Hydrocortisone activity was maximally enhanced at concentrations between 10(-9) M and 10(-8) M, levels that are comparable to plasma levels of hydrocortisone not bound to plasma proteins. Glycyrrhetinic acid had no effect on the suppression of GM-CSF release by hydrocortisone in the transformed cell line BEAS-2B, which does not express the 11betaHSD enzyme. Glycyrrhetinic acid also had no effect on the inhibition of GM-CSF release in PBECs by the synthetic glucocorticoids budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide, steroids not metabolized by 11betaHSD. Together, these findings suggest that metabolism of hydrocortisone by 11betaHSD may regulate glucocorticoid activity in human airway epithelial cells.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Regulation of the action of hydrocortisone in airway epithelial cells by 11beta-hydroxysteroid dehydrogenase. 1046 Jul 58

We have investigated hepatic expression and glucocorticoid regulation of the corticosteroid-binding globulin (CBG) gene in mice lacking a functional glucocorticoid receptor (GR). GR-/- mice show impaired negative feedback in the hypothalamic-pituitary-adrenal axis, resulting in elevated circulating levels of ACTH and corticosterone. This is seen in the neonatal period and continues into adulthood where ACTH and corticosterone levels are increased up to 4-5 fold. Despite high elevation of corticosterone we find no change in mean arterial blood pressure in GR-/- mice and no change in the renal activity of the glucocorticoid-metabolising enzymes 11beta-hydroxysteroid dehydrogenase type-1 (HSD1) and type-2 (HSD2). We do find markedly increased hepatic expression of CBG with a 50% increase in plasma CBG levels. Increased expression of CBG was detected in adult GR-/- mice and also at birth with a greater than 10-fold increase in CBG hepatic mRNA in day-18.5 embryonic GR-/- mice. Adult GR-/- mice were also resistant to dexamethasone-induced repression of CBG expression in the liver. These results indicate that in mice, GR is essential for maintaining the basal level of CBG gene expression in the liver, and is also required for dexamethasone-induced repression of the CBG gene in the adult.
Mol Cell Endocrinol 1999 Aug 20
PMID:The glucocorticoid receptor is essential for maintaining basal and dexamethasone-induced repression of the murine corticosteroid-binding globulin gene. 1050 97


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