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Query: UNIPROT:P06889 (Mol)
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The success in synthesis of [3H]5-androstene-3,17-dione, the intermediate product in the transformation of DHEA to 4-androstenedione by 3 beta-hydroxysteroid dehydrogenase/5-ene----4-ene isomerase (3 beta-HSD) offers the opportunity to determine whether or not the two activities reside in one active site or in two closely related active sites. The finding that N,N-dimethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) inhibits competitively and specifically the dehydrogenase activity whereas a non-competitive inhibition type with a Ki value 1000 fold higher was observed for the isomerase activity, indicated that dehydrogenase and isomerase activities belong to separate sites. Using 5 alpha-dihydro-testosterone and 5 alpha-androstane-3 beta, 17 beta-diol, exclusive substrates for dehydrogenase activity, it was shown that dehydrogenase is reversible and strongly inhibited by 4-MA and that thus the irreversible step in the transformation of DHEA to 4-androstenedione is due to the isomerase activity.
J Steroid Biochem Mol Biol 1991
PMID:Differential inhibition of dehydrogenase and 5-ene----4-ene isomerase activities of purified 3 beta-hydroxysteroid dehydrogenase. Evidence for two distinct sites. 183 46

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHA) and DHA-sulfate are abundantly produced adrenal steroids, whose serum concentrations exceed those of other adrenal steroids. Serum concentrations of DHA and DHA-sulfate, in contrast to other adrenal steroids, exhibit a progressive age-related decline. The mechanism(s) for this selective decline in serum DHA and DHA-sulfate levels and the biologic function of these steroids remain unknown. Studies examining insulin's regulation of adrenal androgens are reviewed. These studies show that experimentally-induced hyperinsulinemia lowers serum DHA and DHA-sulfate levels, and suggest that insulin reduces serum concentrations of these steroids by inhibiting production rather than by increasing clearance. Studies examining the actions of short-term pharmacologic DHA administration to young nonobese and obese men are also reviewed. These studies suggest that DHA may possess hypolipidemic and, possibly, anti-obesity properties. They have failed, however, to demonstrate any effect of DHA on tissue insulin sensitivity.
J Steroid Biochem Mol Biol 1991
PMID:Metabolism and actions of dehydroepiandrosterone in humans. 183 49

1. Using [3H]DHA and unlabeled L-alprenolol, a substantial amount of over 64% specific binding of beta-adrenergic receptor has been identified on the neuroblastoma x glioma hybrid NG108-15 cell, which has been proven to display numerous functional characteristics of intact neurons. 2. Beta-adrenergic receptor binding on intact NG108-15 cells does not change significantly upon morphological differentiation, induced by 1 mM dibutyryl cyclic AMP (dBcAMP). 3. The [3H]DHA binding on intact NG108-15 cells is rapid, saturable, and reversible, having a t1/2 of 1.0 min for association and 3.5 min for dissociation. 4. The affinity constant (Kd) and maximum binding capacity (Bmax) for binding of [3H]DHA to beta-adrenergic receptors on NG108-15 cells have been estimated by Scatchard plot analysis to be 2.5 and 0.23 nM, respectively. Further analysis indicates a single class of receptors for [3HDHA binding on NG108-15 cells. 5. Studies on kinetic properties have revealed on-rate (K + 1) and off-rate (K - 1) constants of 0.7 X 10(-9) M min-1 and 0.19 min-1, respectively. Further, the IC50 value and inhibition constant (Ki) for unlabeled L-alprenolol to inhibit [3HDHA binding on NG108-15 cells have been estimated to be 10(-5) and 8.9 X 10(-6) M, respectively. 6. The rank-order potency of catecholamine agonists, (-)ISO greater than (+)ISO greater than EPI greater than NE, reveals the presence of type 2 receptor for the beta-adrenergic binding on both differentiated and undifferentiated NG108-15 cells. 7. The present study indicates that the clonal neuroblastoma x glioma hybrid NG108-15 cell line possesses substantial amounts of beta-adrenergic receptors with characteristics similar to those on neuronal cells.
Cell Mol Neurobiol 1990 Sep
PMID:Identification and characterization of the beta-adrenergic receptor on neuroblastoma x glioma hybrid NG108-15 cells. 217 41

Serum sulphates of 5-androstene-3 beta,17 beta-diol (5-ADIOL-S), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-DIOL-S) and dehydroepiandrosterone (DHEA-S), as well as 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (3 alpha-DIOL-G) and unconjugated androstenedione (AD) and testosterone (T), sex hormone binding globulin (SHBG), free androgen index (FAI) and 17 alpha-hydroxyprogester-one (17OHP) were measured by specific radioimmunoassays (RIA) in 14 women with late-onset 21-hydroxylase deficiency (LOCAH), and in normal women (n = 73). The diagnosis of LOCAH was made on the finding of a (17OHP) response level greater than 30 nmol/l following ACTH stimulation, and/or an elevation of urinary metabolites of 17OHP. Mean values for serum concentrations of all steroids measured and the free androgen index (100 X T nmol/l divided by SHBG nmol/l) were significantly elevated, and SHBG levels depressed in patients with LOCAH. These studies show that in LOCAH, in addition to the unconjugated steroids AD and T, the sulphoconjugated steroids DHEA-S, 5-ADIOL-S and 3 alpha-DIOL-S are increased, as is the glucuronide conjugate 3 alpha-DIOL-G and the index of bioavailable testosterone (FAI), and that mean SHBG levels are depressed. These data suggest that as well as AD, 5-ADIOL-S and DHEA-S may act as pro-hormones for more potent steroids (T and 5 alpha-dihydrotestosterone) in peripheral tissues, while 3 alpha-DIOL-S and 3 alpha-DIOL-G may both reflect peripheral androgen metabolism in patients with LOCAH.
J Steroid Biochem Mol Biol 1990 Nov 30
PMID:Serum levels of 5-androstene-3 beta,17 beta-diol sulphate, 5 alpha-androstane-3 alpha, 17beta-diol sulphate and glucuronide, in late onset 21-hydroxylase deficiency. 217 25

[3H]Dihydroalprenolol ([3H]DHA) has been used extensively in receptor binding studies to measure beta-adrenergic receptors in the central nervous system. Usually, nonspecific binding has been defined by high concentrations of the beta-adrenergic receptor agonist isoproterenol or antagonists such as alprenolol or propranolol. Scatchard plots of such "specific" [3H]DHA saturation data in rat cerebral cortex membranes are linear. However, computer analysis demonstrated that the competition curves of these drugs for 2.0 nM [3H]DHA binding are biphasic, with a continuous inhibition of [3H]DHA binding in the concentration range usually used to determine nonspecific binding. These data indicate that another saturable high affinity site was being labeled by the radioligand and that the definition of nonspecific binding with any of these unlabeled drugs is not satisfactory. We used the nonlinear, least squares, curve-fitting program LIGAND to analyze total [3H]DHA binding, allowing the program to mathematically define nonspecific binding as a function of 3H-ligand concentration. Significantly lower Bmax (-44%) and Kd (-58%) values for beta-adrenergic receptors were found, indicating that under normal experimental procedures (defining [3H]DHA non-specific binding with these nonradioactive drugs) a second binding site was being labeled. We found that [3H]DHA binding to this site could be inhibited by drugs such as RU24969, a 5-hydroxytryptamine1A (5HT1A) and 5HT1B receptor subtype-selective agonist, and CGS12066B, a 5HT1B receptor subtype-selective agonist, which were able to compete for 15-20% of [3H]DHA binding in the nanomolar concentration range, whereas drugs that are selective for other serotonin receptor subtypes inhibited [3H]DHA binding only at much higher concentrations. Another beta-adrenergic receptor antagonist radioligand, [3H]CGP-12177, was found to be more selective for beta-adrenergic receptors. Alprenolol competition curves for [3H]CGP-12177 binding were monophasic and saturation curves, with nonspecific binding defined either by 10 microM alprenolol or by LIGAND, yielded Bmax values close to those obtained with [3H]DHA when its nonspecific binding was defined by LIGAND. [3H]DHA cannot be considered a suitable radioligand to quantify central nervous system beta-adrenergic receptors in the manner in which it has been typically used.
Mol Pharmacol 1989 Jul
PMID:Comparison of two putatively selective radioligands for labeling central nervous system beta-adrenergic receptors: inadequacy of [3H]dihydroalprenolol. 254 50

Treatment of rats with desipramine (DMI) has been shown to down-regulate beta-adrenergic receptor-stimulated adenylate cyclase and reduce the Bmax of beta-adrenergic receptors in some brain areas. Recent reports have indicated that the down-regulation in the number of beta-adrenergic receptors following DMI treatment does not occur if the serotonin system has been impaired following parachlorophenylalanine (PCPA) or 5,7-dihydroxytryptamine injection. We have previously shown that [3H]dihydroalprenolol ([3H]DHA), the most commonly used radioligand to measure central nervous system beta-adrenergic receptors, labels another site under normal experimental procedures, in addition to the beta-adrenergic receptors. This second site has some pharmacological characteristics of the 5-hydroxytryptamine1A receptor. The depletion of serotonin following PCPA injection was indeed able to prevent the down-regulation of [3H]DHA binding sites after DMI injection. However, PCPA alone increased the density of [3H]DHA binding sites. If the nonlinear, least squares, curve-fitting program LIGAND was allowed to define [3H]DHA nonspecific binding or if the more selective beta-adrenergic receptor radioligand [3H]CGP-1277 was used, the Bmax of beta-adrenergic receptors was not changed after PCPA injection. Importantly, PCPA did not prevent beta-adrenergic receptor down-regulation following DMI treatment. The blockade of 5-hydroxytryptamine2 receptors, via ketanserin administration, during DMI treatment did not change the response of beta-adrenergic receptors. Furthermore, if LIGAND was used to define the nonspecific binding of [3H]DHA, the down-regulation of beta-adrenergic receptors was significant 24 hr after a single DMI injection. The same rapid down-regulation was demonstrated with [3H]CGP-12177. However, if [3H]DHA was used to label beta-adrenergic receptors in the "typical" manner (nonspecific binding defined by 10 microM alprenolol), a decrease in the number of beta-adrenergic receptors was significant only after seven daily DMI injections. These data demonstrate that the use of [3H]DHA to measure beta-adrenergic receptors can be misleading, because changes in its second binding site can conceal the changes occurring in beta-adrenergic receptors. Moreover, these results suggest that a similarity in the time course of action of DMI cannot be used to support the hypothesis that its therapeutic antidepressant action is related to beta-adrenergic receptor down-regulation.
Mol Pharmacol 1989 Jul
PMID:Reevaluation of the regulation of beta-adrenergic receptor binding by desipramine treatment. 254 51

Since there is convincing evidence for a role of adrenal steroids as precursors of active sex steroids in peripheral tissues, especially prostate cancer, we have studied the effect of the four main adrenal steroids, namely dehydroepiandrosterone sulfate (DHEA-S), DHEA, 5-androstene-3 beta,17 beta-diol (delta 5-diol) and 4-androstene-3,17-dione (delta 4-dione) on the growth of an androgen-sensitive clone (SEM-1) of the mouse mammary carcinoma Shionogi. From a control doubling time of 6.69 +/- 0.03 days, 0.1 microM DHT, 1.0 microM delta 4-dione, 10 microM delta 5-diol, 10 microM DHEA-S and 10 microM DHEA decreased generation time to 1.60 +/- 0.01, 1.69 +/- 0.01, 1.95 +/- 0.01, 4.37 +/- 0.02 and 5.66 +/- 0.03 days, respectively (P less than 0.01 vs. control). The same compounds exerted their stimulatory effects on cell growth at the following ED50 values: 0.06 nM, 16 nM, 90 nM, 150 nM and 16 microM for DHT, delta 4-dione, DHEA, delta 5-diol and DHEA-S, respectively. The stimulatory effect of all compounds was inhibited in a competitive manner by the pure antiandrogen hydroxyflutamide. Further evidence for an action of the adrenal steroids through the androgen receptor is indicated by competition of [3H]testosterone uptake in the tumor cells at the following IC50 values: 0.21 nM, 0.63 nM, 50 nM, 75 nM and 680 nM for DHT, testosterone, delta 4-dione, delta 5-diol and DHEA, respectively. The present data show that the four main adrenal steroids present in the serum of adult men can exert potent stimulatory effects on the growth of an androgen-sensitive cancer cell line through an androgen receptor-mediated mechanism.
Mol Cell Endocrinol 1988 Aug
PMID:Adrenal precursor C19 steroids are potent stimulators of growth of androgen-sensitive mouse mammary carcinoma Shionogi cells in vitro. 297 15

Changes in the population of adrenergic alpha- and beta-receptors were examined in rat soleus muscles during hypokalemia by their direct determination using radiolabeled ligands. Only beta-adrenoceptors were detected in the normal rat muscles. Hypokalemia led to a pronounced decrease in beta-adrenoceptors, the number of [3H]DHA binding sites, by 50%, as compared with that in the normal rats. There was a genesis of alpha 1-adrenoceptors in hypokalemic rat muscles, since the competitive potency of adrenergic drugs against [3H]prazosin binding was in the order prazosin much greater than phentolamine greater than (+/-)-noradrenaline greater than yohimbine much greater than (+/-)-isoproterenol. The reduction of [3H]DHA binding sites was accompanied by an increase of an approximately equal amount in high-affinity [3H]prazosin binding sites. The Kd determined by kinetic analysis of [3H]prazosin binding was calculated from the ratio K-1/K1 that gave a value of 3.05 nM, which generally agreed with the 1.83 nM determined by saturation experiments (Scatchard plot). This phenomenon of a reduction in the beta-adrenoceptors and the occurrence of alpha 1-adrenoceptors in muscles during hypokalemia is discussed. alpha- and beta-adrenoceptors on soleus muscle membrane may play important but opposite roles in modulating potassium release from the muscle cells.
Cell Mol Neurobiol 1986 Sep
PMID:Hypokalemia modulates alpha- and beta-adrenoceptor bindings in rat skeletal muscle. 302 29

Three groups of male, weanling, Sprague-Dawley rats were fed diets containing 7% hydrogenated coconut oil, 6.6% hydrogenated coconut oil + 0.4% corn oil, or 7% corn oil for 8-17 weeks. These diets provided 0% (EFAD group), 0.5% (MEFAD group) or 5% (CONTROL group) of the total energy as linoleic acid, respectively. Crude plasma membranes were prepared from heart and assayed for adenylate cyclase activity. Both basal and fluoride-stimulated activity was lower in the membranes from EFAD and MEFAD rats than that of the controls. The double bond index of total lipids and phospholipids, and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) were not appreciably different in the membranes from the three dietary groups. The fatty acid composition of total phospholipids of the membranes, however, was quite different and indicative of biochemical changes typical of an EFA deficiency. Feeding of the control diet to the EFAD or MEFAD rats for up to 6 weeks did not alleviate completely the changes in adenylate cyclase activity although the fatty acid patterns were restored to the normal levels. There was also a decrease in the number of [3H]-DHA binding sites in heart of EFAD rats as compared with their controls. The results suggest that the changes induced by EFA deficiency in the acyl group composition of membrane phospholipids and in the number of beta-adrenergic receptors may be important in regulating adenylate cyclase activity in the heart.
J Mol Cell Cardiol 1987 May
PMID:Adenylate cyclase activity, membrane fluidity and fatty acid composition of rat heart in essential fatty acid deficiency. 362 82

Using (-)-[3H]-dihydroalprenolol ([3H]-DHA) and [3H]-norepinephrine ([3H]-NE) as probes, adrenoreceptors in mouse and rabbit adipocyte plasma membranes were studied and compared. The binding of either radioligand can be displaced by propranolol, alprenolol, isoproterenol or norepinephrine. [3H]-Norepinephrine bound to rabbit plasma membrane can be displaced by phentolamine. Based on displacement of radioligand by unlabelled stereoisomers, the binding is stereospecific for the (-) stereoisomer. Quantitative binding determinations of catecholamine radioligand as well as competitive inhibitory and displacement studies with Scatchard plots where appropriate, allowed calculation of binding parameters including Bmax and Kd for both radioligands and for the compounds listed above. Kinetics of displacement were also followed. Based on these binding parameters and kinetics, together with the activity of hormone and NaF sensitive adenylate cyclase, we conclude that both the population of beta-adrenoreceptor and its coupling efficiency for adenylate cyclase of the rabbit plasma membrane appear to be low as compared to that of mouse and rat.
Mol Cell Biochem 1981 Jan 20
PMID:Response of white adipocyte of mouse and rabbit to catecholamines and ACTH. 3. Modified binding properties of beta-adrenoreceptor and its decreased coupling efficiency for adenylate cyclase. 626 27


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