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)

A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin activity and the aldosterone concentration were low, while the DOC concentration was high (6.10-10.3 ng/ml; normal range 0.03-0.33). Plasma cortisol, androgens, and estrogens as well as urinary 17-OHCS and 17-KS were within normal limits. Furosemide administration and two hours upright posture resulted in a 3-fold increase in plasma DOC, but the administration of ACTH, dexamethasone, or angiotensin III had no effect on plasma DOC. Following resection of a right adrenal tumor weighing 70 g, the hypertension and hypokalemia disappeared. DOC content in the tumor was high. On light microscopic examination, the tumor was encapsulated, composed of cells with clear cytoplasm and large nuclei and there were extensive areas of fibrosis and infiltration of lymphocytes. According to Weiss's criteria, the tumor was considered to be an adrenocortical adenoma. Immunohistochemically, P450scc, 3 beta HSD, P450C21 and P45011 beta were positive with heterogeneity of intra-tumoral expression. No immunoreactivity for P45017 alpha in this adenoma was detected. This is different from a previous report in which a relatively small number of cells in DOC-secreting adrenocortical carcinoma were positive for P45017 alpha.
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PMID:A case of deoxycorticosterone-producing adrenal adenoma. 857 86

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

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
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PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

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

The expression of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) has been demonstrated in the adrenal glands, but until now little attention has been paid on its possible physiologic action. In-situ perfused rat adrenals released under basal conditions, in addition to mineralo- and glucocorticoids, notable amounts of 11-dehydrocorticosterone (DH-B), the inactive form to which corticosterone (the main glucocorticoid in rodents) is converted by 11 beta-HSD. The addition to the perfusion medium of glycyrrhetinic acid, a specific inhibitor of 11 beta-HSD, strongly reduced DH-B release and simultaneously evoked a moderate rise in both mineralo- and glucocorticoid output. The bolus administration of ACTH strikingly enhanced mineralo- and glucocorticoid secretion, but it significantly depressed DH-B release Rat adrenal microsome preparations possessed 11 beta-HSD activity, that was inhibited by glycyrrhetinic acid. Conversely, ACTH was without any apparent effect, a finding indicating that the in vivo observed ACTH-induced inhibition of adrenal 11 beta-HSD activity is mediated by an indirect mechanism whose elucidation requires further investigation. In conclusion, our present findings suggest that adrenal 11 beta-HSD plays a role in the regulation of steroid secretion in rats under both basal and stimulated conditions.
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PMID:Intra-adrenal 11 beta-hydroxysteroid dehydrogenase plays a role in the regulation of corticosteroid secretion: an in vitro study in the rat. 889 Sep 18

Cortisol, produced by the primate fetal adrenal, regulates the maturation of organ systems necessary for extrauterine life. During most of primate pregnancy, however, the fetal adrenal lacks the enzyme 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), which is essential for cortisol synthesis. Therefore, we used immunohistochemistry and in situ hybridization techniques to investigate the developmental expression of 3 beta HSD in the fetal rhesus monkey adrenal from 109 days' gestation until term (165 +/- 5 days) and assessed the role of ACTH in the induction of its expression and localization. We also examined whether ACTH regulates the expression of two other steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage (P450scc) and P450 17 alpha-hydroxylase, 17/20-lyase (P450c17), in the fetal rhesus monkey adrenal. To stimulate ACTH secretion from the fetal pituitary in vivo, we administered metyrapone to late gestation fetal rhesus monkeys for 3-7 days. Adrenals were collected from untreated fetuses at 109-125 days (n = 5), 130-148 days (n = 7), 155-172 days (n = 4), and after metyrapone treatment at 135-137 days (n = 4). The cortical width and total amount of 3 beta HSD staining were measured using an image analysis system. 3 beta HSD was localized primarily in the definitive zone cells of the adrenal from fetuses between 109-148 days, whereas at term (155-172 days), 3 beta HSD was localized in both definitive and transitional zone cells. The cortical width and total amount of 3 beta HSD staining in the adrenal increased significantly (P < 0.05) between 148 days (137 +/- 14 microns and 3,689 +/- 522 grains) and 155 days (315 +/- 61 microns and 7,321 +/- 2,008 grains). Interestingly, in metyrapone-treated fetuses at 135-137 days, 3 beta HSD messenger RNA (mRNA) and protein were localized extensively in both the definitive and transitional zones, a pattern seen only in term fetal adrenals in untreated animals. In addition, metyrapone treatment significantly (P < 0.05) increased cortical width (386 +/- 95 microns) and total 3 beta HSD immunostaining (29,063 +/- 13,692 grains) compared with age-matched controls. In contrast to 3 beta HSD, P450scc mRNA was detected in the definitive, transitional, and fetal zones, and its expression was not altered after metyrapone treatment. P450c17 mRNA was detected in the transitional and fetal zones, and the relative abundance was greater in the transitional zone. The relative abundance of P450c17 mRNA was increased in the fetal zone after metyrapone treatment. In summary, at term or after metyrapone treatment, expression of 3 beta HSD is induced in the transitional zone of the fetal rhesus monkey adrenal gland, an indication of functional maturation of the primate adrenal cortex. These data suggest that the ontogenetic increase in fetal pituitary ACTH secretion plays an important role in the induction of 3 beta HSD expression in the transitional zone.
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PMID:Functional maturation of the primate fetal adrenal in vivo. II. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3 beta-hydroxysteroid dehydrogenase/isomerase. 889 68

Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated delta 5 precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-hydroxypregnenolone (delta 5-17P) in all PP subjects, at 2.2-17 SD for dehydroepi-androsterone (DHEA) and 2.4-5.6 SD for the delta 5-17P/cortisol (F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/ androstenedione (delta 5-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for delta 5-17P in all 13 PP children, at 2.3-4.7 SD for the delta 5-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9 SD for the DHEA/delta 4-A ratio in 7 PP children. Type II 3 beta HSD gene sequences, including regions of a putative promoter, all exons (I, II, III, and IV), and exon-intron boundaries, were normal in all subjects. Sequences of the type I 3 beta HSD gene encoding extraadrenal and extragonadal 3 beta HSD were normal in the 6 patients tested. The ACTH-stimulated delta 5-17P levels and delta 5-17P/F ratios in the PP children without type II 3 beta HSD gene mutation were exceedingly lower than the respective reported hormonal data for children with 3 beta HSD deficiency CAH with proven type II 3 beta HSD gene mutation. The ACTH-stimulated DHEA levels and DHEA/delta 4-A ratios were not exceedingly different between the children with and without type II 3 beta HSD gene mutation. These findings suggest that the degree of ACTH-stimulated delta 5 precursor steroid abnormality, such as delta 5-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation. The hormonal criterion for ACTH-stimulated delta 5-17P levels in patients with mild variant 3 beta HSD deficiency, therefore, is predicted to be higher than 10 SD above the normal mean value.
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PMID:Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels. 892 44

Previous studies in ovine adrenocortical cells in vitro have shown angiotensin II (AII) receptors are expressed on the zona fasciculata (ZF) cells and are functionally coupled to phosphoinositidase C and increased [Ca2+]i, but AII stimulation does not cause an acute change in cortisol biosynthesis. AII can, however, chronically regulate differential expression of P450c17 and 3 beta HSD in ovine adrenocortical cells in vitro. We have stained ovine adrenal sections with specific antisera to the angiotensin II Type-1 receptor (AT1-R), as well as P450c17 and 3 beta HSD in order to further test the hypothesis that changes in AT1-R expression underlie changes in zonal expression of P450c17 and 3 beta HSD in vivo. AT1-R expression was found to be highest in the outermost layer of cells (zona glomerulosa, ZG) which stained negatively for P450c17 and only faintly positive for 3 beta HSD, as expected. The adjacent layer of cells (ZF) stained much less strongly for AT1-R but stronger for P450c17 and 3 beta HSD. These findings are consistent with our previously reported in vitro expression data, and suggest that the transition from ZG to ZF phenotype, i.e. increased P450c17 and 3 beta HSD expression, may require reduced expression of AT1-R, but maintenance of reduced levels of AT1-R expression in the ovine ZF still allows for differential control of the P450c17: 3 beta HSD ratio. Thus, even though there is no acute cortisol response to AII alone in these cells, AII stimulation can oppose C19 steroid production in the face of cortisol biosynthesis by the ZF in response to agonists such as ACTH.
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PMID:Immunohistochemical analysis of AT1 receptor versus P450c17 and 3 beta HSD expression in ovine adrenals. 896 82

Nonclassic or the mild form of 3 beta-hydroxysteroid dehydrogenase (NC3 beta-HSD) deficiency is an entity which is identified with typical features of premature pubarche, hirsutism, or oligomenorrhea. In this study, type II 3 beta-HSD gene from 4 girls who were diagnosed as NC3 beta-HSD deficient, base on the adrenal steroidogenic responses to ACTH, was analyzed to determine whether NC3 beta-HSD deficiency was an allelic variant of classical 3 beta-HSD deficiency by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). We could not detect any alterations of type II 3 beta-HSD gene from these patients. Our result strongly suggests that unlike classical 3 beta-HSD deficiency, NC3 beta-HSD deficiency may be secondary adrenal biosynthetic defects, rather than dual inherited deficiencies.
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PMID:No genetic mutation in type II 3 beta-hydroxysteroid dehydrogenase gene in patients with biochemical evidence of enzyme deficiency. 903 Sep 67

We have previously shown a decrease in fetal zone-specific ACTH-stimulable dehydroepiandrosterone formation and an increase in definitive zone-specific cortisol biosynthesis in the baboon fetal adrenal gland in the second half of gestation. Therefore, the fetal and definitive zones seem to develop a divergence in functional capacity with advancing gestation. We have proposed, therefore, that there is a selective decrease in ACTH receptor expression and thus tropic responsivity to ACTH within the fetal zone in the second half of primate pregnancy. The present study examined this possibility and whether corresponding changes occurred in the developmental expression of major components required for steroidogenesis. ACTH receptor messenger RNA (mRNA) levels, determined by in situ hybridization, in the fetal zone of the baboon fetal adrenal were approximately 2-fold greater (P < 0.05) at mid (i.e. day 100) than at late (i.e. day 170) gestation and 3-fold greater (P < 0.01) in the definitive zone than in the fetal zone in late gestation (term = 184 days). Both ACTH receptor and low density lipoprotein receptor mRNA levels, determined by Northern blot in the whole fetal adrenal, also decreased (P < 0.001) by approximately 50%, whereas the mRNA levels for the definitive zone-specific delta5-3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) enzyme required for cortisol biosynthesis increased over 13-fold (P < 0.001) between mid and late gestation. In contrast, mRNA expression of the steroidogenic enzymes P-450 cholesterol side-chain cleavage and 17alpha-hydroxylase/17-20 lyase were unchanged throughout gestation. We conclude that the decrease in ACTH receptor mRNA expression and ACTH-stimulable dehydroepiandrosterone formation in the second half of gestation reflect a decline in functional capacity of the fetal zone, whereas the increase in 3beta-HSD mRNA expression and cortisol production results from the ACTH receptor-mediated development and enhanced functional capacity of the definitive zone.
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PMID:Decline in adrenocorticotropin receptor messenger ribonucleic acid expression in the baboon fetal adrenocortical zone in the second half of pregnancy. 907 25


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