Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)isomerase (3beta-HSD) isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. The 3beta-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. In humans, there are two 3beta-HSD isoenzymes, which were chronologically designated type I and II encoded by HSD3B1 and HSD3B2 gene, respectively. HSD3B1 gene encodes the almost exclusive 3beta-HSD isoenzyme expressed in the placenta and peripheral tissues, whereas HSD3B2 gene encodes the predominant 3beta-HSD isoenzyme expressed in the adrenal gland, ovary, and testis and its deficiency is responsible for a rare form of congenital adrenal hyperplasia causing various degrees of salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. Although an elevated ratio of Delta(5)-Delta(4)-steroids was considered to be the best biological parameter for the diagnosis of this autosomal recessive disorder, the most accurate criteria now appears to be the plasma levels of 17-OH-pregnenolone greater than 100 nmol/L following ACTH stimulation. To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing, and 23 missense mutations) have been identified in the HSD3B2 gene in 56 individuals from 44 families suffering from classical 3beta-HSD deficiency. In almost all the cases, the functional characterization of HSD3B2 mutations has provided a molecular explanation for the heterogeneous clinical presentation of this disorder. Indeed these experiments confirm that no functional 3betaHSD type II isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form, whereas the non-salt-losing form results from specific missense mutation(s) in the HSD3B2 gene, which causes an incomplete loss of enzymatic activity thus leaving sufficient enzymatic activity to prevent salt wasting. Moreover, various mutations appear to have a drastic effect upon stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3beta-HSD deficiency. Thus, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily.
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PMID:Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency. 1242 6

Glucocorticoids indirectly alter adrenocortical steroid output through the inhibition of ACTH secretion by the anterior pituitary. However, previous studies suggest that glucocorticoids can directly affect adrenocortical steroid production. Therefore, we have investigated the ability of glucocorticoids to affect transcription of adrenocortical steroid biosynthetic enzymes. One potential target of glucocorticoid action in the adrenal is an enzyme critical for adrenocortical steroid production: 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD). Treatment of the adrenocortical cell line (H295R) with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3beta-HSD mRNA levels alone or in conjunction with phorbol ester. This increase in 3beta-HSD mRNA was paralleled by increases in Steroidogenic Acute Regulatory Protein (StAR) mRNA levels. The human type II 3beta-HSD promoter lacks a consensus palindromic glucocorticoid response element (GRE) but does contain a Stat5 response element (Stat5RE) suggesting that glucocorticoids could affect type II 3beta-HSD transcription via interaction with Stat5. Transfection experiments show enhancement of human type II 3beta-HSD promoter activity by coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with 100nM dexamethasone. Furthermore, removal of the Stat5RE either by truncation of the 5' flanking sequence in the promoter or introduction of point mutations to the Stat5RE abolished the ability of DEX to enhance 3beta-HSD promoter activity. These studies demonstrate the ability of glucocorticoids to directly enhance the expression of an adrenal steroidogenic enzyme gene albeit independent of a consensus palindromic glucocorticoid response element.
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PMID:Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene. 1242 39

Glucocorticoids are regulated at the prereceptor level by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11 beta-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11 beta-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11 beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11 beta-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9)M (65 +/- 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9) M (65 +/- 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11 beta-HSD-1 mRNA expression. TNF alpha up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (140 +/- 20%; P < 0.001); the same cytokine increased 11 beta-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 +/- 14% of control (P < 0.01). IL-1 beta also up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (160 +/- 33%; P < 0.001) and caused an increase in glycerol levels (159 +/- 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol up-regulated 11 beta-HSD-1 activity maximally at 10(-7) M (162 +/- 46%; P < 0.02), and clonidine down-regulated it at 10(-7) M (82 +/- 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11 beta-HSD-1 might include down-regulation of 11 beta-HSD-1 activity by CRH, ACTH, and alpha 2 sympathetic stimulation, and up-regulation of the enzyme by beta 2 sympathetic stimulation and by the cytokines TNFalpha and IL-1 beta.
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PMID:Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. 1251 81

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.
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PMID:Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig. 1255 67

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase.
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PMID:Effects of S-petasin on corticosterone release in rats. 1281 4

Glucocorticoids (GCs) are a vital class of steroid hormones that are secreted by the adrenal cortex and that are regulated by ACTH largely under the control of the hypothalamic-pituitary-adrenal axis. GCs mediate profound and diverse physiological effects in vertebrates, ranging from development, metabolism, neurobiology, anti-inflammation and programmed cell death to many other fuctions. Multiple factors "downstream" of GC secretion, such as glucocorticoid receptor (GR) number and the abundance of plasma binding proteins have originally been considered as modulators of GC action. However, in the last decade the role of tissue-specific GC activating and inactivating enzymes have been identified as additional determinants in GC signalling pathways. On the cellular level, they function as important pre-receptor regulators by acting as "molecular switches" for receptor-active and receptor-inactive GC hormones. According to their biologic activity to catalyze the interconversion of C11-hydroxyl and C11-oxo GCs these enzymes have been named 11beta-hydroxysteroid dehydrogenase (11beta-HSD; EC 1.1.1.146). Two isoforms of 11beta-HSD have been cloned and characterized so far. 11beta-HSD type 1 is found in a wide range of tissues, acts predominantly as a reductase in intact cells and tissues by regenerating active cortisol from cortisone, and has been described to regulate GC access to the GR. 11beta-HSD type 2 is found mainly in mineralocorticoid target tissues such as kidney and colon, acts only as a dehydrogenase by producing inactive cortisone, and has been found to protect the mineralocorticoid receptor from high levels of receptor-active cortisol. Recently, 11beta-HSD 1 has become highly topical due to the finding that 11beta-HSD 1 plays a pivotal role in the pathogenesis of central obesity and the appearance of the metabolic syndrome. This review provides an overview on the components involved in GC signalling of 11beta-HSD type 1 as an important pre-receptor control enzyme that modulates activation of the GR.
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PMID:Enzymology and molecular biology of glucocorticoid metabolism in humans. 1460 13

In this study, the expression of several genes involved in cortisol synthesis in head kidneys, the site of cortisol production, and in the rainbow trout (Oncorhynchus mykiss) was examined in response to two different acute stressors and an acute ACTH treatment. mRNAs levels of the "steroidogenic acute regulatory" (StAR) sterol transport protein, which transports cholesterol to the inner mitochondrial membrane as well as cytochrome P450 cholesterol side chain cleavage (P450(SCC)) were determined in head kidney (containing the interrenal tissue). In one experiment, we also quantified 3-beta-hydroxysteroid dehydrogenase (3B-HSD) and cytochrome P450(11beta) (11B-H) mRNAs. The presence of these four transcripts in the head kidney was confirmed by Northern blot analysis. For each stress condition, mRNA levels were quantified by quantitative or real-time RT-PCR. The results of these two methods were highly correlated. An acute stress induced by capture, short confinement (2min), and anesthesia (3min) resulted in significant elevation of plasma cortisol (30-fold higher than controls) and an increase in levels of StAR and P450(SCC) mRNAs 3h post-stress. When fish were submitted to an acute stress caused by 5min of chase with a net in a tank, plasma cortisol reached a peak within 1h, but after 3h, levels were only 5-fold higher in stressed trout than in controls and no variations in the expression of StAR, P450(SCC), 3B-HSD, and 11B-H were observed whatever the time post-stress. One hour after acute ACTH stimulation (5IU/kg), plasma cortisol level was 4-fold higher than in control trout and no changes in StAR and P450(SCC) mRNAs levels were detected. The data suggest that the high levels of cortisol after stress need an activation of genes involved in cortisol synthesis, but lower levels do not. Futhermore, under these three test conditions, we always found a strong positive correlation between mRNA levels of StAR and P450(SCC), in contrast to what has been described in mammals. Consequently, the absence of transcription activation with low increase in cortisol levels suggests that other levels of regulation, particularly activation of pre-existing proteins, govern cortisol production.
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PMID:Relationship between changes in mRNAs of the genes encoding steroidogenic acute regulatory protein and P450 cholesterol side chain cleavage in head kidney and plasma levels of cortisol in response to different kinds of acute stress in the rainbow trout (Oncorhynchus mykiss). 1464 46

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.
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PMID:Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. 1467 Nov 89

Late onset congenital adrenal hyperplasia (LO CAH) can be seen in association with polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). The study aimed to find out the prevalence of LO CAH in Central Anatolia among hirsute women. Sixty-three patients with hirsutism were evaluated to determine the frequency of LO CAH by comparing them with their age and body mass index matched 28 healthy controls. Of those 63 hirsute women, 43 were diagnosed as PCOS, and 20 were diagnosed as IH. Following basal hormonal evaluation, all subjects underwent ACTH stimulation test and ACTH stimulated 17-hydroxyprogesterone (17-OH P), 11-desoxycortisol (11-DOC), cortisol (F), and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in all subjects. ACTH stimulated 17-OH P, 11-DOC, and DHEA-S levels did not differ between groups. However, stimulated F levels were found to be higher in hirsute women (p<0.001). Six out of 63 (9.52%) patients with hirsutism met the criterion for 21 hydroxylase deficiency. We found no subject presumed to have 11-beta hydroxylase deficiency, but one subject in control group (3.57%) and two patients among PCOS subjects (4.65%) had exaggerated DHEA-S response which was suggestive of mild 3-beta hydroxysteroid dehydrogenase deficiency. In conclusion, the most frequent form of LO CAH seems to be due to 21 OH deficiency among women with PCOS and IH in Central Anatolia. Mild 3-beta HSD deficiency may also be an underlying cause for hirsutism and it may be seen without any clinical presentation. Adrenal hyperactivity is likely to be the main reason of hyperandrogenemia in women with hirsutism.
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PMID:The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia. 1470 56

Neonatal human males produce high levels of dehydroepiandrosterone (DHEA) and its sulfo-conjugated form (DS) that decline within a few months of birth, due to regression of the adrenal fetal zone (FZ). Adult male humans and rhesus monkeys produce C19 steroids in abundance from the adrenal zona reticularis (ZR). Male marmoset monkeys produce DS at birth, but unlike humans and rhesus monkeys, do not produce comparable amounts of DHEA and DS in adulthood. To determine whether male marmosets express a functional ZR in adulthood, we examined adult and neonatal male marmosets for the presence of a ZR and FZ, respectively. Exogenous ACTH failed to stimulate DHEA or DS in adults, and dexamethasone treatment failed to suppress DHEA and DS, although cortisol levels changed as expected. In steroidogenic tissues, the key proteins necessary to synthesize C19 steroids from pregnenolone are P450c17, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), nicotinamide adenine dinucleotide phosphate (reduced) oxido-reductase cytochrome P450 (reductase), and cytochromeb5 (cytb5). Adult adrenal cross sections showed P450c17 and reductase protein expression throughout the cortex but showed no expected decrease in 3beta-HSD and increase in cytb5 in the innermost region. Western analysis confirmed these data, demonstrating comparable P450c17 expression to rhesus monkeys, but not cytb5. HPLC analysis revealed similar 17alpha-hydroxylase action on pregnenolone for adult marmoset and rhesus adrenal microsomes but greatly diminished 17,20-lyase activity in marmosets. Neonatal marmoset adrenals exhibited staining indicative of a putative FZ (with P450c17, reduced 3beta-HSD and increased cytb5). We conclude that neonatal marmosets exhibit a C19 steroid-secreting FZ similar to humans, but adult males fail to acquire a functional ZR.
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PMID:Male marmoset monkeys express an adrenal fetal zone at birth, but not a zona reticularis in adulthood. 1545 22


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