Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of genes encoding pro-opiomelanocortin (POMC), glucocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) was studied in sheep fetuses during development. POMC mRNA was present in the anterior pituitary by day 60 of gestation (term approximately 145 days), and its relative amount did not change significantly until after days 125-130. The amount of POMC mRNA in the pituitary increased significantly at days 138-143, remained high at term and increased further in newborn lambs. In contrast, POMC mRNA could not be detected in the hypothalamus and adrenal glands of fetuses at all ages studied. These results suggest that the prepartum rise in plasma adrenocorticotrophin (ACTH) concentrations in sheep fetuses is due to increased expression of POMC gene in the pituitary. The number of glucocorticoid receptors, but not the amount of glucocorticoid receptor mRNA changed significantly with gestational age in the hypothalamus, anterior pituitary and adrenal glands of the fetus. Changes in glucocorticoid receptor content of fetal tissues may reflect alterations in translation of glucocorticoid receptor mRNA, subsequent modifications, or glucocorticoid receptor turnover or a combination of these factors. However, in newborn lambs, amounts of glucocorticoid receptor mRNA increased significantly in the hypothalamus and pituitary but decreased to undetectable amounts in the adrenal glands, indicating that tissue-specific factors may influence expression of glucocorticoid receptor gene in neonatal sheep. The interconversion of cortisol and cortisone requires 11 beta-HSD. Since cortisone is biologically inactive, 11 beta-HSD may regulate the activity of intracellular cortisol. We cloned and sequenced a cDNA encoding sheep 11 beta-HSD. By northern blot analysis, this cDNA detected a single 1.8 kb transcript in the fetal and adult sheep liver, lung, hypothalamus, anterior pituitary and placenta. This could not be detected in the adrenal glands and kidneys, but a smaller (1.5 kb) transcript was present in the fetal and adult kidneys. During fetal development, the relative amount of 11 beta-HSD mRNA did not change significantly in the kidney and lung, but increased in lungs from newborn lambs. In contrast, amounts of hepatic 11 beta-HSD mRNA not only increased significantly in the fetus at term but also displayed a further increase in the newborn. These results clearly indicate that expression of ovine 11 beta-HSD gene in the fetus and newborn is regulated in a tissue-specific and developmentally programmed manner.
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PMID:Regulation of gene expression in the ovine fetus. 133 59

Apparent mineralocorticoid excess (AME) is a rare form of low renin hypertension caused by deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme responsible for conversion of cortisol to the bio-inactive metabolite, cortisone. This results in prolonged cortisol half-life, activation of type I (mineralocorticoid) receptors by cortisol, sodium and fluid retention, and consequent childhood-onset hypertension. The cortisol secretion rate is low, perhaps due to cortisol's binding to type II (glucocorticoid) receptors and suppressing corticotropin secretion. Patients with AME thus lack stigmata of Cushing's syndrome. To evaluate any potential contribution of the type II (glucocorticoid) receptor to the development of hypertension in AME patients, we administered RU486, a steroid analogue that acts as a pure type II receptor blocker. Selective glucocorticoid receptor blockade did not decrease blood pressure in our patient; instead, a significant increase in average blood pressure was observed (125.1 +/- 1.7 pre-RU486 v 144.7 +/- 1.2 during RU486 treatment, P = .0001). We conclude that the type II receptor does not contribute to the development of hypertension in patients with AME.
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PMID:Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. 839 54

In ectopic adrenocorticotropin (ACTH) syndrome (EAS) with higher ACTH levels than in pituitary Cushing's syndrome and during ACTH infusion, the ratio of cortisol to cortisone in plasma and urine is increased, suggesting inhibition of renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) by ACTH or by ACTH-dependent steroids. Measuring the conversion of cortisol to cortisone by human kidney slices under different conditions, we tested the possibility of 11 beta-HSD regulation by ACTH and corticosteroids. Slices prepared from unaffected parts of kidneys removed because of renal cell carcinoma were incubated with unlabeled or labeled cortisol, and cortisol and cortisone were quantitated after HPLC separation by UV or radioactive detection. The 11 beta HSD activity was not influenced by incubation with increasing concentrations (10(-12)-10(-9) mol/l) of ACTH (1-24 or 1-39) for 1 h. Among 12 ACTH-dependent steroids tested (10(-9)-10(-6) mol/l), only corticosterone (IC50 = 2 x 10(-7) mol/l), 18-OH-corticosterone and 11 beta-OH-androstenedione showed a significant dose-dependent inhibition of 11 beta-HSD activity. The percentage conversion rate of cortisol to cortisone was concentration dependent over the whole range of cortisol concentrations tested (10(-8) - 10(-5) mol/l. A direct inhibitory effect of ACTH on 11 beta-HSD is, therefore, unlikely. The only steroids inhibiting the conversion of cortisol to cortisone are natural substrates for 11 beta-HSD. Kinetic studies show a saturation of the enzyme at high cortisol concentrations. Thus, the reduced percentage renal cortisol inactivation in EAS seems to be due mainly to overload of the enzyme with endogenous substrates (cortisol, corticosterone and others) rather than to direct inhibition of 11 beta-HSD by ACTH or ACTH-dependent steroids, not being substrates of 11 beta-HSD.
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PMID:Human kidney 11 beta-hydroxysteroid dehydrogenase: regulation by adrenocorticotropin? 861 21

We have proposed that estrogen, via regulation of the placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzyme(s) catalyzing the oxidation of cortisol to its inactive metabolite cortisone, regulates the baboon fetal pituitary-adrenocortical axis and the onset of de novo production of cortisol by the fetus near term. In support of this hypothesis we have demonstrated that the increase in expression of the mRNA for the ACTH precursor proopiomelanocortin (POMC) in the fetal pituitary and in the specific activity of steroidogenic enzymes in the fetal adrenal normally observed at term were enhanced at midgestation by maternal estrogen administration. However, it is not known whether activation of the fetal pituitary reflects a concomitant increase in corticotropin-releasing hormone (CRH) mRNA expression and/or peptide production by the fetal hypothalamus. Therefore, an aim of the present study was to determine whether the increase in POMC mRNA in fetal baboons delivered at term, and at midgestation to mothers treated with estradiol, reflected an increase in hypothalamic CRH. Fetal hypothalami were obtained on Day 100 (n = 6) and Day 165 of gestation (term = Day 184) from untreated baboons (n = 5) and on Day 100 from baboons (n = 4) whose mother had been treated daily with 1.0 mg estradiol on Days 70 to 100. Hypothalamic CRH peptide concentrations were determined by RIA, and CRH mRNA expression was quantified by in situ hybridization in sections of the fetal hypothalamus through the paraventricular nucleus (PVN) using a 48-base synthetic oligodeoxynucleotide probe 3' end-labeled with [35S]dATP. The mean (+/- SE) maternal serum estradiol concentration in baboons treated with estradiol at midgestation (2.4 +/- 0.4 ng/ml) was greater (p < 0.05) than that in untreated baboons on Day 100 (1.0 +/- 0.2), but similar to that in late gestation (2.0 +/- 0.2). The mean steady-state concentration of CRH in the baboon fetal hypothalamus at midgestation (15.8 +/- 6.0 ng/g tissue) was not altered in fetuses whose mothers had been treated with estradiol (17.6 +/- 0.9 ng/g). Hypothalamic CRH concentrations in fetal baboons of late gestation (20.7 ng/g; n = 2) were also similar to mean CRH values measured at midgestation but, owing to the marked increase in weight of the fetal hypothalamus with advancing pregnancy, the content of hypothalamic CRH in late gestation (28.8 ng/structure) exceeded (p < 0.01) that at midgestation. Mean levels of CRH mRNA at midgestation when expressed per cell (17.4 +/- 1.3 grains per cell) or per unit area of PVN (375 +/- 20 grains per area) were similar to respective values in late gestation (18.3 +/- 1.1 grains per cell; 350 +/- 55 grains per area; n = 3 per group). These findings support the suggestion that the increase in fetal pituitary POMC mRNA expression and ACTH peptide previously reported to occur normally between midgestation and term are not associated with a concomitant increase in hypothalamic CRH peptide or CRH mRNA concentrations. Moreover, it would appear that by midgestation, hypothalamic CRH is available in adequate concentrations to "drive" the fetal pituitary and that it is the levels of maternal cortisol arriving within the fetal circulation, as dictated by estrogen-regulated placental 11 beta-HSD-oxidase activity, that establish the extent to which the fetal pituitary responds to CRH.
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PMID:Hypothalamic corticotropin-releasing hormone expression in the baboon fetus at mid- and late gestation. 886 72

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11 beta-hydroxylase or 17 alpha-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
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PMID:Inherited forms of mineralocorticoid hypertension. 895 79

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.
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PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer. 988 91

The human placenta contains two types of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The exclusive oxidase 11beta-HSD2 has been suggested to protect the fetus from high levels of maternal glucocorticoids by converting cortisol to inactive cortisone. Perfused term human placenta was used to examine the activity of the oxoreductase 11beta-HSD1 and to determine the regulation of cortisol effects on placental vascular tone and corticotropin-releasing hormone (CRH) output by 11beta-HSD. Radioimmunoassay showed that there was substantial cortisol (295+/-57 nM) detected in the fetal vein upon perfusion of cortisol (2 microM; perfusion rate, 12 ml/min) into the maternal intervillous space. Output of cortisol increased to 559+/-22 nM on the fetal side (P<0.05) with concurrent perfusion of carbenoxolone (CBX; 1 microM), a non-specific 11beta-HSD inhibitor. Cortisol formation increased in a dose-dependent manner with infusion of cortisone (0.1-2 microM) into the maternal intervillous space reaching 15 and 23 nM in fetal and maternal venous outflows respectively at 2 microM cortisone perfusion. There was no significant effect of cortisol either alone or in combination with CBX on the fetal arterial perfusion pressure, but cortisol perfusion increased CRH output into the fetal vein. It is concluded that activities of both 11beta-HSD1 and -2 are demonstrable in perfused human placenta in vitro, and these enzymes affect transplacental glucocorticoid transfer. These activities may provide a precise mechanism to control the passage of maternal glucocorticoids to the fetal circulation, and to regulate glucocorticoid effects within the placenta.
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PMID:Interconversion of cortisol and cortisone by 11beta-hydroxysteroid dehydrogenases type 1 and 2 in the perfused human placenta. 995 Jan 40

Corticotrophin releasing factor (CRF) and beta-endorphin (beta EP) containing neurons are shown to be present in the hypothalamus and both neurons are found at the paraventricular nucleus (PVN). Steroid hormones have been found to alter the plasma level of these neurotransmitters. Glycyrrhizic acid (GCA) is the active component of liquorice. GCA inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase (11HSD) which is needed for the inactivation of the steroid pathway, so therefore would cause changes to these neurons. The aim of this study was to investigate the effects of GCA as well as deoxycorticosterone (DOC) and dexamethasone (DM) on the modulation of CRF and beta EP containing neuron at the PVN of the hypothalamus. Rats were given either DM, DOC or GCA and adrenalectomized (ADX) and given either DM or DOC. At the end of treatment rats were transfused transcardially before sacrifice and the brain were dissected for immunohistochemical analysis. We found that immunostaining of the CRF containing neurons demonstrate a reduction in the number of positive neurons in DM treated rats. DOC and GCA treated rats showed the same result as in DM rats but the reduction is less. ADX, DM, DOC and GCA treated rats did not show any changes in the number of beta EP containing neurons but naloxone increased the number of beta EP containing neurons markedly. In conclusion, GCA and DOC have similar effects on CRF and beta EP containing neurons at the PVN.
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PMID:Effects of glycyrrhizic acid and steroid treatment on corticotropin releasing factor and beta-endorphin containing neurons of the hypothalamus of the rat. 1087 79

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.
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PMID:Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms. 1092 94

To continue our studies on the cutaneous expression of a proopiomelanocortin/corticotropin-releasing hormone system, we investigated whether this is accompanied by adrenal-type enzymatic activity. Immortalized cultured human keratinocytes were incubated with radiolabeled corticosteroids. Analysis by thin-layer chromatography showed rapid transformation of both progesterone and deoxycorticosterone; one of the progesterone metabolites migrated at the same rate as deoxycorticosterone. Gas chromatography/mass spectrometry further identified as major species of deoxycorticosterone metabolites 3beta,6alpha,21-trihydroxy-5alpha-pregnan-20-one, 3alpha,6alpha,21-trihydroxy-5alpha-pregnan-20-one, and 3alpha5alpha- and 3beta5alpha-tetrahydrodeoxycorticosterone. Minor metabolites were 3alpha,21-dihydroxy-5-pregnen-20- one (3alphaDelta5-21-OHpregnenolone), 3beta,21-dihydroxy-5-pregnen-20-one (3betaDelta5-21-OHpregnenolone), 3alpha,21-dihydroxy-4-pregnen-20-one (3alphaDelta4-21-OHpregnenolone), 6-hydroxy-dihydrodeoxycorticosterone, and two 5-dihydrodeoxycorticosterone species. Thus, in addition to sex steroids keratinocytes also actively metabolize corticosteroids along similar enzymatic pathways. The surprising detection of 3alphaDelta5-21-OHpregnenolone and 3 betaDelta5-21-OHpregnenolone, indicating Delta4-ketosteroids to Delta5-hydroxysteroids conversion, provides strong evidence for the occurrence, at least in human keratinocytes, of isomerase activity that allows the reaction to proceed in reverse of its usual direction. As skin expresses 3alpha/beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerases, cutaneous reactions catalyzed by these enzymes must be reversible. In conclusion, besides elements of the corticotropin-releasing hormone/proopiomelanocortin system human keratinocytes show high levels of corticosteroid metabolizing activity. Moreover, the wide array of steroid products generated from a single substrate indicates serial progressive conversion involving 5alpha-reductase, 6alpha-hydroxylase, 3alpha/beta-hydroxysteroid dehydrogenase, and reverse Delta4minus signDelta5 isomerase enzymes. As distinct from the adrenal cortex, production of A, B, Aldo, 18OHdeoxycorticosterone, or F in keratinocytes was absent or below limits of detectability.
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PMID:Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes. 1184 49


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