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)

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) is a microsomal enzyme that catalyzes the reversible interconversion of receptor-active 11-hydroxy glucocorticoids (cortisol) to their receptor-inactive 11-oxo metabolites (cortisone). However, the physiological role of 11beta-HSD 1 as prereceptor control device in regulating access of glucocorticoid hormones to the glucocorticoid receptor remains obscure in light of its low substrate affinities, which is in contrast to low glucocorticoid plasma levels and low Kd values of the receptors to cortisol. To solve this enigma, we performed detailed kinetic analyses with a homogeneously purified 11beta-HSD 1 from human liver. The membrane-bound enzyme was successfully obtained in an active state by a purification procedure that took advantage of a gentle solubilization method as well as providing a favorable detergent surrounding during the various chromatographic steps. The identity of purified 11beta-HSD 1 was proven by determination of enzymatic activity, N-terminal amino acid sequencing, and immunoblot analysis. By gel-permeation chromatography we could demonstrate that 11beta-HSD 1 is active as a dimeric enzyme. The cDNA for the enzyme was cloned from a human liver cDNA library and shown to be homologous to that previously characterized in human testis. Interestingly, 11beta-HSD 1 exhibits Michaelis-Menten kinetics with cortisol and corticosterone (11beta-dehydrogenation activity) but cooperative kinetics with cortisone and dehydrocorticosterone (11-oxoreducing activity). Accordingly, this enzyme dynamically adapts to low (nanomolar) as well as to high (micromolar) substrate concentrations, thereby providing the fine-tuning required as a consequence of great variations in circadian plasma glucocorticoid levels.
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PMID:11 Beta-hydroxysteroid dehydrogenase type 1 from human liver: dimerization and enzyme cooperativity support its postulated role as glucocorticoid reductase. 1184 Dec 41

In amphibians, aldosterone (Aldo) is particularly important in the regulation of Na(+) exchange by skin and urinary bladder. In previous works we studied a key enzyme in Aldo biosynthesis, the 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD/I), in the interrenals of Bufo arenarum. In those works a dual localization of the 3 beta HSD/I in both microsomes and mitochondria was described. The mitochondrial, but not the microsomal, enzyme prefers the immediate Aldo precursor, 3 beta-analogue of aldosterone, as substrate. In this order, the enzyme 3 beta HSD/I would be not only a key enzyme for the synthesis of Aldo but additionally, due to its microsomal and mitochondrial localization, a possible target for the regulation of Aldo biosynthesis. With this rationale in mind, we have used in vivo and in vitro approaches to study Aldo regulation. In the present investigation the levels of Aldo were determined in plasma of winter (W) and summer (S) toads subjected to different saline concentrations (0.125 and 0.15 M) or kept on wet land. Saline hyperosmotically treated toads had significantly lower levels than isoosmotically treated toads. These results are consistent with the response in mammals, in which salt loading provokes a reduction in Aldo secretion. In W toads, plasmatic corticosterone (B) concentration was higher than Aldo concentration, whereas in S toads, B/Aldo ratio approached unity. The reduction of Aldo levels after saline dehydration was due to a decline in its biosynthesis. K(m) and V(max) values for 3 beta HSD/I were calculated for mitochondrial and microsomal fractions obtained from animals acclimated to 0.15 M NaCl or kept on land. As previously described, V(max) differs between W and S toads. However, only mitochondrial V(max) changed as a consequence of saline adaptation, suggesting that the mitochondrial enzyme could be involved in the regulation of Aldo biosynthesis.
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PMID:Effect of salt acclimatization on 3 beta-hydroxysteroid dehydrogenase/isomerase activity in the interrenal of Bufo arenarum. 1194 68

Inhibitory effects of flavonoid phytochemicals, flavones, flavonols and isoflavones on cortisol production were examined in human adrenal H295R cells stimulated with di-buthylyl cAMP. In addition, the inhibitory effects of these chemicals on the activity of P450scc, 3beta-HSD type II (3beta-HSD II), P450c17, P450c21 and P45011beta, steroidogenic enzymes involved in cortisol biosynthesis, were examined in the same cells. Exposure to 12.5 microM of the flavonoids 6-hydroxyflavone, 4'-hydroxyflavone, apigenin, daidzein, genistein and formononetin significantly decreased cortisol production (by 6.3, 69.6, 47.5, 26.6, 13.8 and 11.3%, respectively), and biochanin A significantly decreased cortisol production (by 47.3%) at a concentration of 25 microM without any significant cytotoxic effects or changes in cell number. Daidzin, the 7-glucoside of daidzein, did not alter cortisol production by H295R cells at concentrations over 10 microg/ml (24 microM). Daidzein-induced reduction of cortisol production by H295R cells was not inhibited by the estrogen receptor antagonist ICI 182,780. The flavonoids 6-hydroxyflavone, daidzein, genistein, biochanin A and formononetin strongly and significantly inhibited microsomal 3beta-HSD II activity at concentrations from 1 to 25 microM, and I(50) values were estimated to be 1.3, 2, 1, 0.5 and 2.7 microM, respectively. In addition, these flavonoids significantly inhibited microsomal P450c21 activity at 12.5 and/or 25 microM. In addition, 6-hydroxyflavone inhibited activity of microsomal P450c17 and mitochondrial P45011beta at 12.5 and/or 25 microM. Results of Lineweaver-Burk's plot analysis indicate that daidzein is a competitive inhibitor of the activity of 3beta-HSD II and P450c21. K(m) and V(max) values of 3beta-HSD II for DHEA were estimated to be 6.6 microM and 328pmol/minmg protein, respectively. K(m) and V(max) values of P450c21 for progesterone were estimated to be 2.8 microM and 16pmol/minmg protein, respectively. K(i) values of 3beta-HSD II and P450c21 for daidzein were estimated to be 2.9 and 33.3 microM, respectively.
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PMID:Effects of flavonoid phytochemicals on cortisol production and on activities of steroidogenic enzymes in human adrenocortical H295R cells. 1194 20

Licorice-derivatives such as glycyrrhizic acid (GA) competitively inhibit 11 beta-hydroxysteroid dehydrogenase(11 beta-HSD) type 2 (11-HSD2) enzymatic activity, and chronic clinical use often results in pseudoaldosteronism. Since the effect of GA on 11-HSD2 expression remains unknown, we undertook in vivo and in vitro studies. Male Wistar rats were given 30, 60 or 120 mg/kg of GA twice a day for 2 weeks. Plasma corticosterone was decreased in those given the 120 mg dose, while urinary corticosterone excretion was increased in those given the 30 and 60 mg doses but decreased in those given 120 mg GA. NAD(+)-dependent dehydrogenase activity in kidney microsomal fraction was decreased in animals receiving doses of 60 and 120 mg GA. The 11-HSD2 protein and mRNA levels were decreased in those given 120 mg GA. In contrast, in vitro studies using mouse kidney M1 cells revealed that 24h treatment with glycyrrhetinic acid did not affect the 11-HSD2 mRNA expression levels. Thus, in addition to its role as a competitive inhibitor of 11-HSD2, the chronic high dose of GA suppresses mRNA and protein expression of 11-HSD2 possibly via indirect mechanisms. These effects may explain the prolonged symptoms after cessation of GA administration in some pseudoaldosteronism patients.
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PMID:Glycyrrhizic acid suppresses type 2 11 beta-hydroxysteroid dehydrogenase expression in vivo. 1198 91

Benfluron (B, [5-(2-N-oxo-2-N',N"-dimethylaminoethoxy)-7-oxo-7H-benzo[c]fluorene]) is a potential benzo[c]fluorene antineoplastic agent with high activity against a broad spectrum of experimental tumors in vitro and in vivo. The structure of B has been modified to repress its rapid deactivation through carbonyl reduction on C7. 3,9-Dimethoxybenfluron (D, [3,9-dimethoxy-5-(2-N-oxo-2-N',N"-dimethylaminoethoxy)-7-oxo-7H-benzo[c]fluorene]) is one of the B derivatives developed. The present paper was designed to compare the C7 carbonyl reduction of B and D in microsomes, cytosol and hepatocytes from human liver. Two purified human enzymes, microsomal 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD 1) and cytosolic carbonyl reductase, were tested if they are responsible for B and D carbonyl reduction in the respective fractions. Indeed, carbonyl reduction of D in comparison to that of B was 4 and 6-10 times less extensive in human liver microsomes and cytosol, respectively. Moreover, about 10-20 times higher amounts of dihydro B than dihydro D were detected in primary culture of human hepatocytes. 11beta-HSD 1 was shown to be able to reduce B and D. For this enzyme, about 10 times higher rates of carbonyl reduction were observed for B than for D. Likewise, CR participates in B and D carbonyl reduction, although smaller amounts of both reduced metabolites were detected. In summary, carbonyl reduction of D was significantly less extensive than that of B in all in vitro experiments. This lower rate of D inactivation was especially pronounced in hepatocytes which represent a close to in vivo situation. Our results clearly demonstrate that dimethoxy substitution protects the carbonyl group of the benzo[c]fluorene moiety against the deactivation by microsomal and cytosolic reductases. Detailed knowledge on the participating enzymes may serve as a basis for the co-application of specific inhibitors in chemotherapy to further improve the pharmacokinetics of benzo[c]fluorene derivatives.
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PMID:Carbonyl reduction of the potential cytostatic drugs benfluron and 3,9-dimethoxybenfluron in human in vitro. 1212 51

Oracin, 6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c] isoquinoline, is a potential cytostatic drug for oral use and presently in phase II of clinical trials. Major advantages of this novel chemotherapeutic are the possibility of oral administration, its negative results in the Ames test on mutagenicity, and the lack of cardiotoxicity. Metabolic studies on oracin have revealed that the principal metabolite in all laboratory animals is 11-dihydrooracin (DHO), which is produced by carbonyl reduction of the parent compound. Since the carbonyl moiety of oracin is a pro-chiral centre, reduction may lead to the two stereoisomer forms (+)-DHO and (-)-DHO. The aim of the present study was to infer if 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) is responsible for carbonyl reduction of oracin in mouse liver and if this enzyme exhibits stereospecificity in DHO formation. 11beta-HSD 1 was purified from mouse liver microsomes, and the kinetics and stereospecificity regarding DHO formation were determined and compared to values obtained from the whole microsomal fraction. We could show that purified mouse liver 11beta-HSD 1 catalyzes the stereospecific carbonyl reduction of oracin, thereby following a sigmoidal dose-response kinetics. Due to a different ratio of (+)-DHO and (-)-DHO (93:7) formed by purified 11beta-HSD 1 compared to that produced in whole microsomes (70:30), the existence of at least one other oracin carbonyl reducing enzyme can be expected in mouse liver microsomes. This suggestion is further supported by the fact that the Hill coefficient of 2 for purified 11beta-HSD 1 (which is supporting earlier data on the cooperativity of this dimeric enzyme) changes to a Hill coefficient of 3 in whole microsomes (which is indicative for another enzyme participating in oracin carbonyl reduction).
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PMID:Stereochemical aspects of carbonyl reduction of the original anticancer drug oracin by mouse liver microsomes and purified 11beta-hydroxysteroid dehydrogenase type 1. 1260 32

To assess the effect of dietary sucrose on liver cytochrome P450 1A content and activity, male F344 rat weanlings were randomized into two diet groups for a period of 90 days. One group was fed a diet containing 65% of total calories from sucrose (HSD) while the other was fed standard lab chow (0% sucrose). Microsomal fractions from each of 10 animals in each group were used in Western immunoblot, mutagenesis and 7-alkoxyresorufin-0-deethylase (AROD) assays. No statistically significant difference in the mean quantity of liver CYP 1A2 was detected by Western blot analysis, while a significant decrease in mean liver CYP 1A1 was observed in the rats fed the HSD. Liver microsomal-dependent mutagenesis of two heterocyclic amines (HCAs), 2-amino-3,8-dimethyl-imadazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), in Salminella typhimurium TA98 was decreased in animals on the HSD compared to those on the control diet by 33% (p < 0.001) and 25% (p < 0.001), respectively. In addition, rats on the HSD had significantly decreased ethoxyresorufin-0-deethylase (EROD) and methoxyresorufin-0-deethylase (MROD) activity over a range of substrate concentrations. These results show that a HSD alters hepatic CYP 1A content and activity and suggests that the metabolism of substrates for this P450 subfamily may be significantly altered.
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PMID:Effect of high sucrose diet on cytochrome P450 1A and heterocyclic amine mutagenesis. 1268 Feb 39

Aflatoxin B1 (AFB1) is a fungal toxin and contaminant that has been implicated in human liver carcinogenesis. In this study we evaluated the effect of a 65% of total calories from sucrose diet (HSD) for 90 days on hepatic cytochrome P450 (CYP450) and glutathione-S-transferase (GST) activity compared to rats maintained on standard lab chow (0% sucrose). There was a statistically significant increase in the number of S. typhimurium His+ revertants (p < 0.001) generated from the incubation of AFB1 with hepatic microsomes from rats fed a HSD. The HSD did not affect the total microsomal CYP450 content nor content of CYP450 1A2, 2B1, 2 isoforms which activate AFB1. Alkoxyresorufin O-dealkylase activity (MROD, PROD) of microsomes from animals fed HSD was decreased by 73% and 49%, respectively. MROD activity is linked to CYP 1A2 activity while PROD is linked to CYP 2B1,2 activity. Although the amount of CYP 3A was significantly decreased in rats fed a HSD, its activity, determined by the presence of the fluorometric metabolite 7-hydroxyquinidine, was unchanged. GST activity was significantly lower in the rats fed HSD.
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PMID:Effect of high sucrose diet on liver enzyme content and activity and aflatoxin B1-induced mutagenesis. 1279 88

In this study, we have examined the effects of a range of organotin compounds (mono-, di-, tributyltin, mono-, di-, trioctyltin) on the activities of rat testis microsomal 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17-hydroxylase (17-OHase) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). 17-OHase activity was inhibited by more than 50% compared with the control rate by 59 microM tributyltin (TBT) but other organotin compounds showed no inhibition. 17beta-HSD activity was unaffected by all organotins tested. 3beta-HSD was inhibited by monooctyltin (81 microM) and by TBT at all concentrations tested in a dose-dependent manner, with almost complete loss of activity at TBT concentrations of 12 microM. The mechanism of inhibition of 3beta-HSD was investigated in kinetic analysis with 0-12 microM TBT. Three rat testis microsomal preparations were incubated with dehydroepiandrosterone as the steroid substrate ranging from 1 to 10,000 nM. Tributyltin was primarily a competitive inhibitor of 3beta-HSD activity, causing an increase in the value of the K(m(app)). However, the mechanism was not entirely competitive as while there was an increase in K(m(app)), a decrease in the V(max(app)) was also observed with increasing concentrations of TBT. Slope and intercept replots demonstrated that the K(i)((app)) from slope replots was around 2.7 microM whereas the K(i)((app)) value from intercept replots was around 30 microM. When compared with the K(m(app)) for 3beta-HSD of around 0.42 microM, TBT could be an effective inhibitor of this enzyme.
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PMID:Inhibition of rat testis microsomal 3beta-hydroxysteroid dehydrogenase activity by tributyltin. 1294 49

Late human gestation is associated with an increase in the concentration of cortisol (F) in the fetal circulation and amniotic fluid. It had been assumed that most of the F measured in the amniotic fluid came from the fetal adrenal gland. However, local production of F can also occur in human intrauterine tissues from inactive cortisone under the influence of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1. Recent studies have shown that 11beta-HSD 1 activity is up-regulated by prostaglandins (PG) E2 and F2alpha, hormones that are produced in the fetal membranes (FM) at term. In the present study, we hypothesized that 11beta-HSD 1 expression would increase in FM during pregnancy and at labor, creating the potential for local increase in F production at term. We examined 11beta-HSD 1 expression in placenta and FM obtained during normal pregnancy from nonlaboring women [26-28 wk (n = 3); 29-30 wk (n = 3); 32-33 wk (n = 3); 35-36 wk (n = 3)] and from uncomplicated term pregnancies after elective cesarean section (n = 6). 11beta-HSD 1 expression was also examined in amnion and chorionic tissues in relation to term labor (n = 12). Immunohistochemistry and Western blot analysis were used to examine 11beta-HSD 1 localization and expression. 11beta-HSD 1 activity was also measured in microsomal fractions prepared from whole fetal membranes. At term, immunoreactive 11beta-HSD 1 expression was localized predominantly to the chorion trophoblast cells, attached decidua, and amnion epithelial cells. 11beta-HSD 1 expression in FM increased with gestational age and reflected increased enzyme reductase activity. No change in 11beta-HSD 1 expression was found in placental tissue from the same patients. There was a significant increase in 11beta-HSD 1 expression in amnion but not in chorion with the onset of labor. We suggest that increases in 11beta-HSD 1 expression/activity by intrauterine membranes during late gestation may result in increased potential for a local increase in F production and that FM should be considered as an extraadrenal source of F during late gestation. This local F production may be involved in different pathways contributing to the regulation of parturition.
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PMID:Late gestation increase in 11beta-hydroxysteroid dehydrogenase 1 expression in human fetal membranes: a novel intrauterine source of cortisol. 1455 91


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