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)

Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) inactivate circulating steroid hormones, and in target tissues regulate the occupancy of steroid hormone receptors. Molecular cloning indicates that 3 alpha-HSDs are members of the aldo-keto reductase (AKR) superfamily and display high sequence identity (> 60%). Of these, the most extensively characterized is rat liver 3 alpha-HSD. X-ray crystal structures of the apoenzyme and the E.NADP+ complex have been determined and serve as structural templates for other 3 alpha-HSDs. These structures reveal that rat liver 3 alpha-HSD adopts an (alpha/beta)8-barrel protein fold. NAD(P)(H) lies perpendicular to the barrel axis in an extended conformation, with the nicotinamide ring at the core of the barrel, and the adenine ring at the periphery of the structure. The nicotinamide ring is stabilized by interaction with Y216, S166, D167, and Q190, so that the A-face points into the vacant active site. The 4-pro-(R) hydrogen transferred in the oxidoreduction of steroids is in close proximity to a catalytic tetrad that consists of D50, Y55, K84, and H117. A water molecule is within hydrogen bond distance of H117 and Y55, and its position may mimic the position of the carbonyl of a 3-ketosteroid substrate. The catalytic tetrad is conserved in members of the AKR superfamily and resides at the base of an apolar cleft implicated in binding steroid hormone. The apolar cleft consists of a side of apolar residues (L54, W86, F128, and F129), and opposing this side is a flexible loop that contains W227. These constraints suggest that the alpha-face of the steroid would orient itself along that side of the cleft containing W86. Site-directed mutagenesis of the catalytic tetrad indicates that Y55 and K84 are essential for catalysis. Y55S and Y55F mutants are catalytically inactive, but still form binary (E.NADPH) and ternary (E.NADH.Testosterone) complexes; by contrast K84R and K84M mutants are catalytically inactive, but do not bind steroid hormone. The reliance on a Tyr/Lys pair is reminiscent of catalytic mechanisms proposed for other AKR members as well as for HSDs that belong to the short-chain dehydrogenase/reductase (SDR) family, in which Tyr is the general acid, with its pKa being lowered by Lys. Superimposition of the nicotinamide rings in the structures of 3 alpha-HSD (an AKR) and 3 alpha, 20 beta-HSD (an SDR) show that the Tyr/Lys pairs are positionally conserved, suggesting convergent evolution across protein families to a common mechanism for HSD catalysis. W86Y and W227Y mutants bind testosterone to the E.NADH complex, with effective increases in Kd of 8- and 20-fold. These data provide the first evidence that the side of the apolar cleft containing W86 and the opposing flexible loop containing W227 are parts of the steroid-binding site. Detailed mutagenesis studies of the apolar cleft and elucidation of a ternary complex structure will ultimately provide details of the determinants that govern steroid hormone recognition. These determinants could provide a rational basis for structure-based inhibitor design.
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PMID:Structure and function of 3 alpha-hydroxysteroid dehydrogenase. 902 23

The reduction of burn edema is a common goal in the resuscitation of patients with thermal injury. Initial infusion of a 2400 mOsm hypertonic 7.5% NaCl 6% dextran (HSD) has been shown to reduce volume needs, but elevated serum sodium levels limit the dose that can be safely used. This study tested the hypothesis that a 2400 mOsm solution of NaCl, amino acids, glucose, and 6% dextran (Isosal-D) would reduce similar volume requirements while maintaining normal plasma sodium levels. Hemodynamics, plasma sodium, fluid balance, and tissue water content were measured after an initial baseline period and during resuscitation of a large scald injury in 21 anesthetized sheep. Resuscitation was begun 30 minutes after the scald with infusion of 10 ml/kg of either lactated Ringer's (LR), Isosal-D, or HSD and was continued with LR to restore and maintain baseline oxygen delivery throughout the 8-hour period. Oxygen delivery, cardiac output, and mean arterial pressure were rapidly reestablished by all three solutions, although a persistent tachycardia was noted with Isosal-D. Net fluid requirements of both HSD (35 +/- 13 ml/kg) and Isosal-D (72 +/- 13 ml/kg) were significantly lower than in the LR group (203 +/- 39 ml/kg). Mean serum sodium increased 11 mEq with HSD to a peak after 4 hours of 152 +/- 5 mEq, whereas with LR sodium fell 7 mEq to 132 +/- 4. Isosal-treated animals had minimal change in serum sodium. HSD significantly decreased tissue water content in colon, liver, pancreas, and nonburned skin compared with LR, whereas Isosal-D reduced edema only in the colon. It is concluded that in this protocol Isosal-D was not as effective as HSD at reducing volume needs and edema and had unexpected chronotropic effects.
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PMID:A comparison of two different 2400 mOsm solutions for resuscitation of major burns. 909 19

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

Cocaine abuse is known to be associated with suppression of the immune system. In this experiment, animals treated with cocaine (CC) in their drinking water (200 mg/L) for 10 days resulted in a significant decrease in thymus weight in HSD-NDA male Swiss mice. A subsequent in-vitro experiment was designed to investigate the direct effect of cocaine and other dopaminergic agents on thymocyte proliferation. Thymus glands were aseptically removed from mice and thymocytes were isolated and then incubated in microtiter plates with various concentrations (10[-8]-10[-4] M) of CC, apomorphine (AM), haloperidol (HP), dopamine (DA) and epinephrine (EN) for 18 hrs. The results revealed that cocaine inhibits [3H]-thymidine uptake into DNA in a dose-dependent manner. Apomorphine, haloperidol and dopamine also exhibited a similar dose dependent inhibition of thymocyte proliferation. The IC25s for DNA synthesis inhibition were 8.2 x 10(-6) M, 4.3 x 10(-7) M, 2.5 x 10(-7) M, and 1.1 x 10(-7) M for CC, HP, DA and AM, respectively. EN was found not to have any significant effect on DNA synthesis. The results suggest that thymus gland atrophy, associated with use of CC may be related to the inhibition of thymocyte proliferation.
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PMID:The thymolytic effect of cocaine and monoaminergic drugs in the mouse. 949 13

Adhesion of restorative and protective materials to dentin is an important requirement for operative and preventive dentistry. Wettability and roughness are dentin substrate conditions that are critical to establishing good adhesion. This study examined superficial and deep dentin for variations in water contact angle measurements and roughness for polished, etched, dehydrated, and rehydrated states. Superficial and deep dentin disks from 6 non-carious third molars were prepared for AFM (Atomic Force Microscope) observation, roughness measurement, and contact angle measurements following specific treatments: hydrated and polished, etched (10% H3PO4), dehydrated (desiccator for 24 hrs); and rehydrated (in water for 24 hrs). Contact angles were measured by means of the ADSA (Axisymmetric Drop Shape Analysis) technique with filtered and purified water of surface tension 72.79 ergs/cm2. The AFM was used to quantify the intertubular roughness. Mean and SD of roughness and contact angle were calculated for each dentin state, and two-way Repeated Measures ANOVA with Tukey's HSD multiple comparisons were performed at p < 0.05. Wetting and roughness both increased after etching, with roughness tending to increase further while wettability dramatically decreased after desiccation. After rehydration, water contact angle values were equivalent to those of the etched condition. Although intertubular roughness did not depend on depth, lower water contact angles were found for deep dentin. Depth and dehydration resulted in altered dentin substrates with exposed hydrophobic moieties that could interfere with bonding to hydrophilic primer coats.
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PMID:Acid-etching and hydration influence on dentin roughness and wettability. 1051 90

Glucocorticoid access to renal corticosteroid receptors is regulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), converting 11beta-hydroxyglucocorticoids into inactive 11-ketones. This mechanism plays a key role in maintaining normal salt-water homeostasis and blood pressure. To study whether renal cortical proximal and distal tubular 11beta-HSDs are modulated, upon shifting the electrolyte status (and may thereby contribute to adjusting the salt-water homeostasis), rats were treated for 14 days with diets with low (0.058 w/w%), normal (0.58%, which is the KCl content of standard European laboratory rat food) or high (5.8%) potassium chloride content. In proximal tubules, dietary KCl had no effect regarding corticosterone 11beta-oxidation in intact cells as well as 11beta-HSD1 and 11beta-HSD2 protein (Western blotting) and mRNA levels (semi-quantitative RT-PCR). In distal tubules, the low KCl diet also had no effect. However, distal tubules of rats fed the high KCl diet showed increased corticosterone 11beta-oxidation rates (1.6-fold, P<0.01) and 11beta-HSD2 protein (4-fold, P<0.01), whereas 11beta-HSD1 protein was decreased (no longer detected, P<0.05). Distal tubular 11beta-HSD mRNA levels were not changed upon dietary treatment. Our results suggest that upon dietary KCl loading distal tubular mineralocorticoid receptor selectivity for aldosterone is increased because of enhanced corticosterone 11beta-oxidation. This may contribute to the fine-tuning of salt-water homeostasis by the kidney.
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PMID:High dietary potassium chloride intake augments rat renal mineralocorticoid receptor selectivity via 11beta-hydroxysteroid dehydrogenase. 1056 68

A key feature in the successful resuscitation of dehydrated or endotoxemic ruminants is the total amount of sodium administered. Administration of small volumes of HS and HSD offer major advantages over large volumes of isotonic saline because HS and HSD do not require intravenous catheterization or periodic monitoring, and are therefore suitable for use in the field. Hypertonic saline and HSD exert their beneficial effect by rapidly increasing preload and transiently decreasing afterload. Contrary to early reports, HS and HSD decrease cardiac contractility and do not activate a pulmonary reflex. The osmolality of HS and HSD should be 2400 mOsm/L (7.2% NaCl solution, 8 times normal plasma osmolality). Use of HS and HSD solutions of different osmolality to 2400 mOsm/L should be avoided at all costs, as too low a tonicity removes the main advantages of HS (low cost, decreased infusion time), whereas too high a tonicity may cause rapid vasodilation and decreased cardiac contractility, resulting in death. Rapid administration (> 1 mL/kg-1/min-1) of HS (2400 mOsm/L) should be avoided, as the induced hypotension may be fatal when coupled with a transient decrease in cardiac contractility. For treating dehydrated adult ruminants, HS (2400 mOsm/L, 4-5 mL/kg i.v. over 4-5 minutes) should be administered through the jugular vein and the cow allowed to drink water. This means that 2 L of HS should be administered to adult cattle. HSD should be administered in conjunction with isotonic oral electrolyte solutions to all calves 8% or more dehydrated (eyes recessed > or = 4 mm into the orbit, cervical skin tent duration > 6 seconds) or calves with reduced cardiac output (fetlock temperature < 29 degrees C when housed at 10-24 degrees C). For treating dehydrated calves, HSD (2400 mOsm/L NaCl in 6% dextran-70, 4-5 mL/kg i.v. over 4-5 minutes) should be administered through the jugular vein and the calf allowed to suckle an isotonic oral electrolyte solution. This means that 120-200 mL of HSD of HSD should be administered to a calf. HSD should be routinely administered to severely depressed or comatose calves, as HSD provides the fastest method of resuscitation while rapidly reversing the effects of hyperkalemia.
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PMID:Hypertonic saline. 1057 12

Effect of arsenic on ovarian steroidogenesis at the dose available in drinking water at wide areas of West Bengal is reported here. Weights of ovary, uterus and vagina along with biochemical activities of ovarian delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) and plasma levels of LH, FSH and estrogen were measured in mature rats of the Wistar strain at diestrous phase following subchronic treatment with sodium arsenite at a dose of 0.4 ppm/rat/day for 16 days (4 estrous cycles) and 28 days (7 estrous cycles). A significant reduction in plasma levels of LH, FSH and estrogen along with significant diminution in the activities of ovarian delta 5-3 beta-HSD and 17 beta-HSD were observed following sodium arsenite treatment for 28 days. This duration of treatment also resulted in a marked degree in diminution in the weights of ovary, uterus and vagina, but 16 days of treatment did not exhibit any significant effect on these above parameters. Arsenic-treated rats exhibited a prolonged diestrous phase in the estrous cycle in contrast to control rats having 4 days of a regular estrous cycle. Deposition of arsenic in ovary, uterus, vagina and plasma was also monitored in arsenic-treated rats. The results of our experiment suggest that duration of arsenic treatment is the critical factor for its adverse effect on ovarian activities at the dose within the range noted in drinking water at several areas of West Bengal in India.
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PMID:Effect of sodium arsenite on plasma levels of gonadotrophins and ovarian steroidogenesis in mature albino rats: duration-dependent response. 1065 65

A high sucrose diet reduces dentin apposition of growing rats. The mechanisms of reduction are unclear, but disturbances in calcium balance or in mineralization of predentin may explain them. In this experiment, 29 Sprague-Dawley rats, 21 days old, were weaned and randomized into calcium-deficient, high-sucrose or standard-diet groups for 3 weeks. They were given food and water ad libitum. During the experiment, animals were individually housed in metabolic cages where urine samples were collected. At ages of 21 and 40 days mineralizing dentin was marked using I.P. injections of oxytetracycline hydrochloride. At 42 days of age, the animals were anesthetized and their blood was collected by cardiac puncture. Right hemimandibles were sectioned sagittally and left hemimandibles were fixed, decalcified, and cut into histological sections. Dentin appositions were measured planimetrically, predentin width, from histological sections. Ca, K, and Na levels of serum and urine were measured flame photimetrically and P levels were measured by the UV method. Statistical analyses were done using one-way analysis of variation (ANOVA) Tuckey's HSD t test. In the calcium-deficient group, hypocalcemia, reduced dentin apposition, and increased predentin width were noticed when compared with the control group (P<0.05). Also, the increase in predentin width, caused by calcium deficiency, was significant compared with sucrose-fed animals (P<0.05). Sucrose diet reduced dentinogenesis, increased Ca excretion to urine, but also reduced urinary levels of P, K, and Na, and the differences were significant for the controls (P<0.05). In conclusion, despite the same kind of reduced dentinogenesis in calcium-deficient and high-sucrose groups, calcium imbalance or reduced mineralization of predentin does not explain reduced dentinogenesis in sucrose-fed animals.
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PMID:The reducing effects of a calcium-deficient diet and high sucrose diet on dentin apposition of rat molars. 1077 9

The fetal environment is now recognized as a key determinant of the adult phenotype, being linked to development of diseases, including hypertension, as well as the timing of puberty. Such links may be related, in part, to the level of fetal exposure to maternal glucocorticoids in utero, which is normally regulated by placental expression of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The present study examined whether manipulation of fetal glucocorticoid exposure, either directly or indirectly via 11beta-HSD inhibition, influences the subsequent timing of puberty. Administration of dexamethasone acetate at low (LDEX, 0.25 microg/ml drinking water) or high doses (HDEX, 1 microg/ml) or carbenoxolone (CBX, 2 x 10 mg/day, sc; an inhibitor of 11beta-HSD) to pregnant rats from day 13 to term (day 23) reduced offspring birthweight (LDEX: 9%; HDEX: 27%; CBX: 8%) and resulted in a subsequent delay in the onset of puberty in females (control: 41.4 +/- 0.5; LDEX: 44.8 +/- 0.7; HDEX: 48.5 +/- 0.4; CBX: 43.6 +/- 0.5 days). Importantly, the effects of CBX were not observed in the absence of maternal adrenals, indicating that they were mediated by increased fetal exposure to endogenous maternal glucocorticoids. In contrast, maternal treatment with metyrapone (MET; an inhibitor of glucocorticoid synthesis; 500 microg/ml drinking water from day 13) increased birthweight by 5% and advanced puberty onset in male offspring (control: 48.8 +/- 1.0; MET: 45.7 +/- 0.8 days). Changes in the timing of puberty onset were not attributable to changes in either bodyweight at puberty or peripubertal plasma leptin concentrations. Peripubertal plasma LH was also unaffected in animals with delayed puberty but was elevated in male offspring of MET-treated mothers. Collectively, these results demonstrate that fetal glucocorticoid exposure is an important determinant of the timing of puberty onset in postnatal life, and that this effect is operable within the normal physiological range of glucocorticoid concentrations.
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PMID:Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. 1087 42


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