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Query: UNIPROT:P06889 (Mol)
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Dehydroepiandrosterone (DHEA) and pregnenolone (PREG) were both metabolized by homogenates of brain, spleen, thymus, perianal skin, ventral skin, intestine, colon, coecum and muscle tissues from mice. The use of 2H-labeled substrates and of the twin ion technique of gas chromatography-mass spectrometry permitted identification of 7 alpha-hydroxy-DHEA and of 5-androstene-3 beta, 17 beta-diol as DHEA metabolites in digests of all tissues. The extent of PREG metabolism was much lower than for DHEA with all tissues but amounts of the main transformation product were sufficient in brain, spleen and ventral skin digests for identification with 7 alpha-hydroxy-PREG. Dimethylsulfoxide (DMSO) solutions of DHEA, PREG and of their 7-hydroxylated metabolites were injected at different doses and time intervals prior to proximal subcutaneous administration of a lysozyme antigen. Quantities of anti-lysozyme IgG were measured in the serum of treated mice and compared with that from sham-treated animals. Increase of anti-lysozyme IgG was obtained with DHEA and PREG (1 g/kg) when injected 2 h prior to lysozyme. Much lower doses (160 times less) of 7 alpha-hydroxy-DHEA and -PREG were also found to be significantly active when administered at the moment of lysozyme injection. A larger dose of 7 beta-hydroxy-DHEA (50 mg/kg) was necessary for a similar effect. These results suggest that in tissues where immune response takes place, the locally-produced 7-hydroxy metabolites of PREG and DHEA are involved in a process which may participate in the physiological regulation of the body's immune response.
J Steroid Biochem Mol Biol 1994 Jul
PMID:Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice. 804 38

Dehydroepiandrosterone (DHEA) decreases the activity of hepatic tyrosine aminotransferase (TAT), a glucocorticoid-inducible enzyme, in the obese, hypercorticosteronemic Zucker rat. To investigate the mechanism of this antiglucocorticoid action, the effect of exogenous DHEA on hepatic glucocorticoid receptor (GC) number and affinity was quantitated. Food supplementation with DHEA (0.6% w/w) for 1 or 7 days had no effect on either receptor number or affinity in obese Zucker rats. After 28 days, however, DHEA treatment resulted in a nearly 40% decrease in cytosolic hepatic receptor content (Bmax; fmol/mg cytosolic protein) without any change in affinity (Kd) in both lean and obese rats. DHEA treatment for 28 days also resulted in an increased liver size and cytosolic protein content. When the hepatic GC receptor content was normalized based on the change in liver size and protein content, the apparent number of GC binding sites per liver was not affected by DHEA treatment. This observation suggests that DHEA's effect on GC receptor content may not be a specific action and that downregulation of the GC receptor is not the mechanism of DHEA action on GC induced TAT activity. This is supported by the effect of DHEA on obese rat TAT activity in the same experiment where the greatest inhibition occurred after only 1 day of treatment. From these experiments it is concluded that although long-term DHEA treatment may decrease the relative concentration of GC receptors in rat liver, this change is not the mechanism through which DHEA mediates its acute antiglucocorticoid action.
J Steroid Biochem Mol Biol 1993 Jun
PMID:Dehydroepiandrosterone regulation of the hepatic glucocorticoid receptor in the Zucker rat. The obesity research program. 810 Jan 44

The effect of long-term glucocorticoid therapy for systemic diseases on glucocorticoid receptor (GR) content and on basal and ACTH-stimulated levels of plasma and salivary cortisol 17 alpha-hydroxy-progesterone, androstenedione, 11 beta-hydroxyandrostenedione, DHEA, its sulfate and sex hormone-binding globulin (SHBG), as well as on basal levels of aldosterone, was investigated in a group of 24 children treated with prednisone for at least 8 months. The therapy was interrupted 24 h before the ACTH test and before plasma and saliva sampling. The control group consisted of 21 healthy children of corresponding age and sex. The patients were divided into two subgroups with normal and subnormal basal cortisolemia, they also differed in their response to ACTH. The GR levels in patient groups were indistinguishable from those found in controls. No correlation was found between GR content and basal levels of the above steroids or their response to ACTH. The best markers, apart from basal cortisolemia, for evaluation of the degree of suppression of adrenal function appeared to be the response of salivary (but not of plasma) cortisol and 17 alpha-hydroxy-progesterone to ACTH. Surprisingly, significantly lower levels of SHBG levels, which rose markedly after ACTH, were found in all the patients.
J Steroid Biochem Mol Biol 1994 Jan
PMID:The effect of long-term glucocorticoid therapy on glucocorticoid receptor content and on steroid response to ACTH. 813 9

The human cytosolic sulfotransferases (STs), dehydroepiandrosterone sulfotransferase (DHEA-ST) and the phenol-sulfating form of phenol sulfotransferase, (P-PST), have been expressed in bacteria and used to investigate the ability of the cloned enzymes to conjugate steroids and related compounds. DHEA-ST was capable of sulfating all of the 3-hydroxysteroids, testosterone and estrogens tested as substrates. The 3-hydroxysteroids, androsterone, epiandrosterone and androstenediol, were conjugated at 50-60% of the rate of DHEA. Of the steroids tested, P-PST was capable of conjugating only the estrogens. The catechol estrogens, 2-hydroxyestradiol, 4-hydroxyestradiol and 4-hydroxyestrone, and compounds with estrogenic activity such as 17 alpha-ethynyl-estradiol and trans-4-hydroxytamoxifen, were also tested as substrates. DHEA-ST showed little or no sulfation activity with these compounds; however, all of these compounds were sulfated by P-PST. These results indicate that the expressed human STs are valuable in analyzing the overlapping substrate specificities of these enzymes and that P-PST may have an important role in the metabolism of estrogens and estrogenic compounds in human tissues.
J Steroid Biochem Mol Biol 1994 Mar
PMID:Steroid sulfation by expressed human cytosolic sulfotransferases. 814 14

The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E1 S) in intact MCF-7 cells (31-85% inhibition at 1 microM and 53-97% inhibition at 10 microM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 microM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the Km and Vmax of E1S were determined to be 8.1 microM and 43 nmol/h/mg protein. The corresponding Ki values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 microM, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.
J Steroid Biochem Mol Biol 1994 Apr
PMID:Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: potential therapeutic agents in breast cancer. 818 Jan 14

The specific activity of 17 beta-hydroxysteroid oxidoreductase (17-HOR) with estradiol-17 beta (E2), estrone (E1) and testosterone (T), as well as that of lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) were measured in homogenates of CF-1 mouse placenta during the latter half of pregnancy. 17-HOR activity with E2 and T increased over 100-fold between days 9 and 12, and 3- to 4-fold between days 15 and 19, with no further change to day 21. In contrast, activity with E1 increased 39-fold between days 9 and 12, 3.8-fold between days 15 and 19 but then decreased between days 19 and 21. The E2/T activity ratio was constant while the E2/E1 ratio increased between days 9 and 21. LDH increased 2-fold between days 9 and 12 with no further increase to day 19. MDH was constant from day 9 to 19. Activity with E2 was inhibited by T, 5 alpha-dihydrotestosterone (5 alpha-DHT) and DHA but not by E1, androstenedione (A) or 20 alpha-dihydroprogesterone. Activity with T was inhibited by E2, 5 alpha-DHT and DHA, but not by A. In contrast, activity with E1 was inhibited by A and DHA but not by E2, T or 5 alpha-DHT. The results suggest placental 17-HOR is developmentally regulated. Although the results are also suggestive of multiple forms of 17-HOR, a single enzyme with an ordered kinetic mechanism cannot be ruled out.
J Steroid Biochem Mol Biol 1993 Jul
PMID:Placental 17 beta-hydroxysteroid oxidoreductase, lactate dehydrogenase and malate dehydrogenase during the latter half of pregnancy in the mouse. 833 91

We observed a boy with ambiguous genitalia and normal testes. Steroid analyses performed during newborn age surprisingly were inconclusive basally and after hCG stimulation, but showed an insufficient testosterone response. Possibly during the early postnatal period the 3 beta-HSD activity in peripheral tissues may have been sufficient to substitute for the deficient 3 beta-HSD activity in the adrenal and gonads. In contrast at 11 and 22 months basal as well as ACTH stimulated levels of 17OHPreg, DHEA and testosterone were typical for a 3 beta-HSD defect.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Male pseudohermaphroditism caused by nonsalt-losing congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency. 848 55

The effects of the constant infusion with mini-osmotic pumps of several steroid hormones on body weight, energy balance and protein/lipid/water composition in young female rats has been studied for a period of 15 days. Despite unchanged food consumption, progesterone strongly induced fat deposition, with higher protein accrual efficiency coupled with lowered energy losses through thermogenesis. Estrogens lowered body weight but maintained higher protein levels and protein accrual rates; beta-estradiol induced the loss of lipid and diminished food intake. Heat production was unchanged or lower in all estrogen-treated animals; beta-estradiol had a more marked effect on body weight (through food intake, heat production and lipid mobilization/storage combined) than estrone. Testosterone and 5-androstenediol increased the proportion of protein, but none of them had a significant effect on lipid deposition or heat production. Nortestosterone, increased energy expenditure, fuelled in part by a higher food ingestion, a trait shared by 4-androstenedione, but not by the other androgens. The effect of androgens on body weight may thus be a combination of their actions on a) food intake, b) efficiency of protein deposition and c) activation of heat production or of lipid (energy) storage. Practically all increased the efficiency of protein deposition. Nortestosterone increased heat production. Androstenedione increased lipid storage. Dehydroepiandrosterone did not decrease body weight or metabolic rate. Cortisol depressed heat production and food intake, with a net loss of weight. Cortisol and cortisone did not increase protein deposition, but corticosterone did; deoxycorticosterone showed a high efficiency of protein deposition and increased the size of fat stores, also increasing the metabolic rate by a mean 26% versus controls, compared with a reduction of about the same magnitude induced by cortisol. The data presented suggest that cortisol-cortisone and corticosterone may represent two distinct groups of glucocorticoids.
Biochem Mol Biol Int 1993 Feb
PMID:Effect of chronic intravenous injection of steroid hormones on body weight and composition of female rats. 849 17

3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD)/delta 5-->4-isomerase activity in steroidogenic tissues is required for the synthesis of biologically active steroids. Previously, by use of dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one, DHEA) as substrate, it was established that in addition to steroidogenic tissues 3 beta-HSD/delta 5-->4-isomerase activity also is expressed in extraglandular tissues of the human fetus. In the present study, we attempted to determine whether the C-5,C-6-double bond of DHEA serves to influence 3 beta-HSD activity. For this purpose, we compared the efficiencies of a 3 beta-hydroxy-5-ene steroid (DHEA) and a 3 beta-hydroxy-5 alpha-reduced steroid (5 alpha-androstane-3 beta,17 beta-diol, 5 alpha-A-diol) as substrates for the enzyme. The apparent Michaelis constant (Km) for 5 alpha-A-diol in midtrimester placenta, fetal liver, and fetal skin tissues was at least one order of magnitude higher than that for DHEA, viz the apparent Km of placental 3 beta-HSD for 5 alpha-A-diol was in the range of 18 to 40 mumol/l (n = 3) vs 0.45 to 4 mumol/l for DHEA (n = 3); for the liver enzyme, 17 mumol/l for 5 alpha-A-diol and 0.60 mumol/l for DHEA, and for the skin enzyme 14 and 0.18 mumol/l, respectively. Moreover, in 13 human fetal tissues evaluated the maximal velocities obtained with 5 alpha-A-diol as substrate were higher than those obtained with DHEA. A similar finding in regard to Kms and rates of product formation was obtained by use of purified placental 3 beta-HSD with DHEA, pregnenolone, and 3 beta-hydroxy-5 alpha-androstan-17-one (epiandrosterone) as substrates: the Km of 3 beta-HSD for DHEA was 2.8 mumol/l, for pregnenolone 1.9 mumol/l, and for epiandrosterone 25 mumol/l. The specific activity of the purified enzyme with pregnenolone as substrate was 27 nmol/mg protein.min and, with epiandrosterone, 127 nmol/mg protein.min. With placental homogenate as the source of 3 beta-HSD, DHEA at a constant level of 5 mumol/l behaved as a competitive inhibitor when the radiolabeled substrate, [3H]5 alpha-A-diol, was present in concentrations of 20 to 60 mumol/l, but at lower substrate concentrations the inhibition was of the mixed type; similar results were obtained with [3H]DHEA as the substrate at variable concentrations in the presence of a fixed concentration of 5 alpha-A-diol (40 mumol/l).(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1993 Jun
PMID:3 beta-hydroxysteroid dehydrogenase activity in tissues of the human fetus determined with 5 alpha-androstane-3 beta,17 beta-diol and dehydroepiandrosterone as substrates. 851 7

The specific effect of docosahexaenoic (DHA; C22:6 n-3), as compared to eicosapentaenoic acid (EPA; C20:5 n-3), on adrenoceptor function was investigated in cultured rat myocardial cells. The cardiomyocytes were grown for 24 h in a conventional seric medium, and then incubated for 96 h in a medium enriched with either DHA or EPA. After this treatment, the phospholipids of the DHA-treated cells contained approximately 20% of the total fatty acids as C22:6 n-3, and those of EPA-treated cells displayed a high content in C20:5 n-3 and its elongation product C22:5 n-3 (30% of total fatty acids). Additionally, the n-3/n-6 polyunsaturated fatty acid ratio was the same in the two groups of cells. These modifications were roughly similar in all the phospholipid classes. The contractions were monitored photometrically and no significant difference in basal frequency and contraction parameters could be detected. The stimulation of the beta-adrenergic receptors (isoproterenol 10(-7) M) resulted in a positive chronotropic effect, which was significantly higher in the DHA-rich cells. Conversely, the higher DHA content in the phospholipids appeared to induce a decrease in the affinity of the beta-receptors for the ligand (dihydroalprenolol) without alteration of the number of beta-receptor binding sites and provoked a significant decrease in isoproterenol-stimulated cAMP production (-19%). To investigate further these controversial data, the cardiomyocytes were treated with dibutyryl-cAMP, which elicited a positive chronotropic response significantly higher in the DHA-rich cells. The alpha-adrenergic stimulation by phenylephrine (3 x 10(-6) M) increased the spontaneous rate, but in a similar manner in the DHA- and EPA-enriched cells. Similarly, neither the alpha-adrenergic receptor binding characteristics nor the production of phosphoinositides was modulated by the membrane DNA content, although the phosphatidylinositol PUFAs were significantly altered. In conclusion, increasing the DHA content in membrane phospholipids did not affect the alpha-adrenergic system, but exerted a specific positive influence on the beta-adrenergic transduction mechanism, essentially through an increase of cAMP efficiency.
J Mol Cell Cardiol 1995 Nov
PMID:Effect of docosahexaenoic acid and eicosapentaenoic acid in the phospholipids of rat heart muscle cells on adrenoceptor responsiveness and mechanism. 859 1


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