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)

Long-term treatment (21 days) of male rats with corticosterone in the drinking water caused a significant increase in the activity of the NADP-dependent form of 11beta-hydroxysteroid dehydrogenase (11-HSD1) in the pituitary, thymus, and spleen, (marginally in the hippocampus, amygdala and lymph nodes), without having any effect in a number of other central and peripheral tissues. In contrast, repeated restraint stress, although increasing plasma corticosterone to the same level as that observed after its administration, failed to change the activity of this key regulatory enzyme, which allows aldosterone to exert its specific effects in the presence of a large excess of corticosterone. This resistance to elevation in 11-HSD activity was also observed in the thymuses of subordinate rats during social stratification in a visible burrow system. In both cases, the circulating levels of corticosterone were much higher in stressed rats than in control animals. Factors which might account for these differences in response are discussed and compared with the situation in intact cells where, unlike in tissue homogenates, the reduction of 11-dehydrocorticosterone to corticosterone (reductase activity) appears to predominate.
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PMID:Long-term corticosteroid treatment but not chronic stress affects 11beta-hydroxysteroid dehydrogenase type I activity in rat brain and peripheral tissues. 921 23

In the present study we have inspected estrogen metabolism in cultured human prostate cancer cells (LNCaP, DU145, PC3), in relation to the expression of mRNAs for different 17 beta hydroxysteroid dehydrogenase (17 beta HSD) enzymes (from 1 to 4). Using an intact cell analysis, we have compared precursor degradation and product formation after incubation of cells with physiological amounts of radioactive E2 or estrone (E1) for 24-72 h and subsequent reverse-phase high performance liquid chromatography analysis. The LNCaP and DU145 cells only partly converted E2 to E1 (26 and 13% at 72 h, respectively), giving rise to an appreciable production of E2 from E1 (nearly 20% in all cases). Conversely, PC3 cells revealed a massive E2 oxidation to E1 (up to 90% by 72 h) and a scant formation of E2 (<2%) from E1. In addition, an appreciable formation of 16 alpha OHE1 was seen in either PC3 (11%) or DU145 (5%) cells. respectively using E2 or E1 as precursor. All three cell lines exhibited marked amounts of 17 beta HSD4 mRNA species, whilst even greater amounts of 17 beta HSD2 transcript were found in PC3 cells only. No mRNA for either 17 beta HSD1 or 17 beta HSD3 could be detected in any cell line. The present evidence indicates that pathways of estrogen metabolism are distinctly governed in prostate cancer cells depending on their endocrine status, being associated with a differential expression of mRNA for different 17 beta HSD enzymes.
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PMID:Molecular expression of 17 beta hydroxysteroid dehydrogenase types in relation to their activity in intact human prostate cancer cells. 925 63

This study was designed to examine the cellular localization and developmental regulation of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1 gene expression in the ovine placenta. Placental tissues were collected at discrete times between days 59 and 143 of pregnancy (term = 145 days). Levels of 11 beta-HSD1 mRNA were determined by Norther blot analysis. The level of both dehydrogenase and reductase activities of 11 beta-HSD1 was assessed by a radiometric conversion assay using cortisol and cortisone as physiological substrates. The cellular localization of 11 beta-HSD1 protein was determined by standard immunohistochemical technique using a polyclonal antibody specific for the ovine protein. High levels of 11 beta-HSD1 mRNA were detected in the placenta by day 59, and there was a trend towards a decrease between days 98-103 and 125-128 (P = 0.06). The level of placental 11 beta-HSD1 mRNA remained unchanged thereafter. Levels of both 11 beta-HSD1 dehydrogenase and reductase activities followed a similar pattern except that in both cases there was a significant decrease between 98-103 and 125-128 (P < 0.05). Moreover, under the present assay conditions, the dehydrogenase activity was always predominant, suggesting that the net effect of placental 11 beta-HSD1 activity would lead to glucocorticoid inactivation. Thus, the decreased 11 beta-HSD1 activity in the placenta at days 125-128 was consistent with, and may help to explain, the apparent increase in the placental transfer of cortisol from mother to fetus during that time. Throughout pregnancy, intense 11 beta-HSD1 immunoreactivity was detected in fetal trophoblastic cells, maternal stromal cells and blood vessels. In contrast, maternal syncytium was immunonegative before day 125, but became immunopositive thereafter. The observed predominant direction of 11 beta-HSD1 activity in vitro and its pattern of localization in the ovine placenta are consistent with the hypothesis that placental 11 beta-HSD protects the fetus from adverse effects of maternal glucocorticoids by inactivating glucocorticoids locally.
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PMID:Cellular localization and developmental regulation of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) gene expression in the ovine placenta. 929 Jan 44

Dahl salt sensitive (Dahl-S) rats develop hypertension soon after birth. The cause of the increased salt-sensitivity in the Dahl-S rat is unknown. The mineralocorticoid specificity of the kidney receptor is conferred by the activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There are two isoforms of 11beta-HSD (11beta-HSD1 and 11beta-HSD2). Deficiency or inhibition of 11beta-HSD2 causes sodium retention and hypertension. In the present study we measured the activity of hepatic and kidney 11beta-HSD1 in Dahl-S and R rats before and after the development of hypertension. The activity of 11beta-HSD1 in the liver was lower in the Dahl-S rats at 6 weeks of age (S = 8.01 +/- 0.89 v R = 11.91 +/- 0.84 nmol/mg protein/10 min (P < .02) but there was no difference at 10 weeks. In contrast, 11beta-HSD1 in the kidney was not different at 6 weeks but it was significantly lower in the Dahl-S rats at 10 weeks (S = 0.91 +/- 0.04 v R = 1.12 +/- 0.01 nmol/mg protein/10 min (P < .001). Plasma renin concentration was lower at 6 (6w) and 10 weeks (10w) in the Dahl-S rats: S-6w = 4.2 +/- 0.4 versus R-6W = 6.3 +/- 0.8 ng angiotensin I (AI)/mL/h (P < .04) and S-10w = 6.4 +/- 0.7 versus R-10w = 10 +/- 0.9 ng AI/mL/h (P < .009). Plasma aldosterone and corticosterone were not different between the two strains. Systolic blood pressure (SBP) in the Dahl-S rats was 124 +/- 3 mm Hg at 6 weeks and 241 +/- 6 mm Hg at 10 weeks (P < .001). SBP in the Dahl-R rats was 113 +/- 5 mm Hg at 6 weeks and 143 +/- 4 mm Hg at 10 weeks. In conclusion, Dahl-S rats have lower hepatic 11beta-HSD1 activity at 6 weeks of age and lower kidney 11beta-HSD1 at 10 weeks of age compared with Dahl-R rats of the same age. These findings suggest that diminished activity of both liver and kidney 11beta-HSD1 may play a role in the salt sensitivity and development of hypertension in the Dahl-S rat.
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PMID:11Beta-hydroxysteroid dehydrogenase in the Dahl rat. 932 6

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) is a potent inactivator of glucocorticoids and is present in high amounts in the placental syncytiotrophoblast and sodium-transporting epithelia. Placental 11 beta HSD2 is thought to protect the fetus from high circulating levels of maternal glucocorticoids, whereas the renal enzyme is important in conferring aldosterone specificity on the mineralocorticoid receptor. An isoform of 11 beta HSD (11 beta HSD1) is also present in a wide range of tissues, but usually acts as an oxoreductase, converting the biologically inactive cortisone to cortisol. In the present study we have used an immunopurified antibody to the carboxy-terminus of human 11 beta HSD2 (HUH23) to demonstrate localization of the enzyme in luminal and glandular epithelia of human endometrium. In some specimens staining was uniformly distributed, but in others there was clear evidence of heterogeneity both between and within epithelia. Although 11 beta HSD2 was found mainly in the cytoplasm, some cells showed evidence of nuclear staining only. Western blot analysis showed a band at 41 kDa in endometrium and myometrium, confirming the presence of 11 beta HSD2. Measurement of activity throughout the menstrual cycle showed that mean levels (+/- SEM) of activity were 156 +/- 17 and 6.1 +/- 1.1 pmol product/min.g homogenate protein for 11 beta HSD2 and 11 beta HSD1, respectively. Patients taking combined estrogen/progesterone contraceptives had significantly lower activities of both enzymes (76 +/- 19 and 1.9 +/- 0.4; both P < 0.01) compared with the control group. 11 beta HSD2 activity was significantly higher in the secretory than in the proliferative phase of the cycle in controls (193 +/- 22 vs. 120 +/- 23; P < 0.05). All groups contained outliers with elevated enzyme activities, with some patients displaying 11 beta HSD2 levels comparable to those observed in human kidney (> 1000 pmol/min.g). Further analysis showed that there was a statistically significant correlation (r = 0.43; P < 0.001) between the levels of 11 beta HSD1 and 11 beta HSD2. There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11 beta HSD2 activities. It remains to be determined whether elevated or suppressed levels of either isoform are associated with fertility or endometrial pathology.
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PMID:11 beta-Hydroxysteroid dehydrogenase type II in the human endometrium: localization and activity during the menstrual cycle. 939 49

The present study was designed to examine the effects of chronic fetal placental embolization on the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, the intracellular enzymes responsible for the metabolism of glucocorticoids. Twelve instrumented fetal sheep were randomly allocated on Day 110 (term = 147 days) to either a control (n = 6) or embolized (n = 6) group. Embolized fetuses received daily injections of nonradioactive microspheres into the abdominal aorta for 21 days to decrease arterial oxygen content by 40-50% of the pre-embolization values. At the end of the experiment, fetal liver and kidney tissues as well as placental cotyledons were collected, and tissue levels of 11beta-HSD mRNA and activity were determined by standard Northern blot analysis and radiometric conversion assay, respectively. There was a 44% reduction (p < 0.01) in the level of renal 11beta-HSD2 mRNA in the embolized group as compared with the control group. Moreover, this reduction in mRNA was carried through to 11beta-HSD2 protein, since there was a corresponding decrease in the level of 11beta-HSD2 activity (4.5+/-0.2 vs. 2.9+/-0.1 pmol/min per milligram protein, p < 0.01). In contrast, levels of both 11beta-HSD1 mRNA and activity in the fetal liver remained unchanged. Moreover, both 11beta-HSD types 1 and 2 mRNA and activity in the placenta were not altered by the fetal placental embolization. In conclusion, chronic hypoxemia selectively inhibits renal 11beta-HSD2 mRNA expression and enzyme activity in the ovine fetus, which may contribute, at least in part, to the mechanisms leading to fetal hypertension.
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PMID:Chronic hypoxemia selectively down-regulates 11beta-hydroxysteroid dehydrogenase type 2 gene expression in the fetal sheep kidney. 947 46

The presence of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity in the kidney has been suggested to be important in the regulation of glucocorticoid-induced disorders of electrolyte balance and the control of blood pressure. To assess the possible effect of 11beta-HSD isoforms in diabetes-related hypertension, we measured the mean systolic blood pressure and the 11beta-HSD activity and mRNA levels for both 11beta-HSD1 and 11beta-HSD2 in the kidney of streptozotocin (STZ)-diabetic female rats. Three weeks after injection of STZ (65 mg/kg), the mean systolic blood pressure of diabetic rats was elevated 13.6% above that of normal rats (P<.01). The renal 11beta-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats (P<.01). However, the treatment of rats with STZ did not decrease the levels of renal 11beta-HSD1 activity and mRNA expression in diabetic rats. Insulin administered subcutaneously to diabetic rats for 2 weeks completely reversed the decrease in renal 11beta-HSD2 activity and gene expression and prevented the elevation in blood pressure in the diabetic rat. These results indicate that alteration of renal 11beta-HSD2 activity and gene expression may be primarily responsible for the changes in blood pressure of STZ-diabetic rats after early treatment with insulin.
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PMID:Gene expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidneys of insulin-dependent diabetic rats. 949 77

Two isozymes of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) are responsible for the interconversion of the active glucocorticoid, cortisol in man, (corticosterone in the rodent), to the inactive 11-keto metabolite, cortisone (11-dehydrocorticosterone). We have examined the regulation of type 1 11 beta-HSD (11 beta-HSD1) using primary cultures of rat and human hepatocytes, both of which express only 11 beta-HSD1. Only 11 oxo-reductase activity could be demonstrated in cultured hepatocytes (apparent Km for cortisone 382 +/- 43 nM in human hepatocytes, apparent Km for 11-dehydrocorticosterone 14.6 +/- 1.5 microM in rat hepatocytes). There exists a marked discrepancy between 11 beta-HSD oxo-reductase activity and 11 beta-HSD1 mRNA levels in cultured human hepatocytes and human liver. Thus oxo-reductase specific activity is much higher in the cultured hepatocytes (7.2 +/- 0.01 nmoles cortisol/mg/h vs 0.89 +/- 0.06 for whole liver homogenates) whilst the converse is true for steady state 11 beta-HSD1 mRNA levels (0.78 +/- 0.02 vs 1.94 +/- 0.07 in whole liver, 11 beta-HSD1/18S expressed as arbitrary units). Carbenoxolone has a significant inhibitory effect on 11 oxo-reductase activity in both rat and human hepatocytes. However, there is clear species-specific regulation of 11 oxo-reductase activity by thyroid hormone (tri-iodothyronine (T3)), which increases 11 oxo-reductase activity in rat hepatocytes but has no effect on activity in human hepatocytes, and progesterone which inhibits activity in human hepatocytes, but has no effect on activity in rat hepatocytes. Neither T3 nor progesterone altered 11 beta-HSD1 mRNA levels. A series of growth factors (hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, transforming growth factor beta 1) were without effect on 11 oxo-reductase activity in cultured rat hepatocytes. In contrast to homogenates of human liver, cultured hepatocytes express only 11 beta-HSD oxo-reductase activity. This is inhibited by carbenoxolone and shows species-specific regulation by T3 and progesterone. Growth factors do not appear to regulate activity or expression of 11 beta-HSD1. The discrepant enzyme activity data and 11 beta-HSD1 mRNA expression in hepatocytes and whole liver could reflect unstable 11 beta-HSD1 oxo-reductase activity or, alternatively, an additional 11 beta-HSD oxo-reductase isoform in cultured hepatocytes.
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PMID:Regulation of 11 beta-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes. 949 45

Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the ontogeny of 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.
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PMID:Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions. 950 16

AME has been a crucial experiment of biology from which much has been learnt about corticosteroid hormone action and mineralocorticoid hypertension. 11 beta-HSD is an important pre-receptor pathway determining corticosteroid hormone action. Any tissue expressing 11 beta-HSD1 or 11 beta-HSD2 can clearly modulate glucocorticoid and mineralocorticoid action independent of circulating concentrations. A series of related enzymes operates in a similar fashion to determine hormone action for other members of the thyroid/steroid hormone receptor superfamily (e.g. 17 beta-HSD, 25-hydroxyvitamin D 1 alpha-hydroxylase, aromatase, 5'-deiodinase, 5 alpha-reductase). Endocrinologists have been obsessed with measuring the concentrations of a hormone in the circulation and making their decisions on the basis of these results, whether or not that hormone is involved in the pathogenesis of a disease process. Such an approach needs to be revised, with greater emphasis on considering the action of a hormone within a given tissue and, in turn, on the role of these enzymes in the pathogenesis of human disease.
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PMID:Cortisol, hypertension and obesity: the role of 11 beta-hydroxysteroid dehydrogenase. 959 34


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