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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spironolactone administration (50 mg/kg/day for 3 days) to make guinea pigs decreased cortisol production by adrenal slices in vitro. Adrenal microsomal and mitochondrial cytochrome P-450 levels were also decreased after treatment with spironolactone. The decline in adrenal cytochrome P-450 content was accompanied by decreases in microsomal 21-hydroxylase and mitochondrial cholesterol side-chain cleavage and 11beta-hydroxylase activities. Activities of other adrenal enzymes, such as delta4-hydrogenase and NADPH-cytochrome c reductase, were unaffected by spironolactone treatment. Cortisone administration to guinea pigs failed to mimic the effects of spironolactone on adrenal function, which indicates specificity of spironolactone action and excludes inhibition of adrenocorticotropin secretion as a mode of action. Addition of spironolactone to isolated adrenal mitochondria or microsomes produced type I spectral changes with spectral dissociation constants similar to those for endogenous steroid substrates. Spironolactone, in vitro, inhibited 11beta- but not 21-hydroxylase activity. The results indicate that spironolactone administration diminishes the activity of adrenal mitochondrial as well as microsomal cytochrome P-450-containing enzymes, resulting in a fall in corticosteroid output.
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PMID:Mechanism of action of spironolactone on adrenocortical function in guinea pigs. 97 70

In the present study we found that 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD), 17-hydroxylase and 17,20-lyase (P-450c17), and 21-hydroxylase (P-450c21) activities in a suspension of cells from guinea pig zona reticularis (RE) were 10- to 15-fold less than those measured in cells from zona fasciculata-glomerulosa (FG). Whereas the secretion of cortisol and C-19 steroids was remarkably increased during treatment of FG cells with adrenocorticotropic hormone (ACTH), no response could be detected when using cells from zona RE. By contrast, the measurement of a series of C-21 and C-19 steroids shows that the concentrations of several steroids were greater in the zona RE than in the zona FG. In addition, using Northern blot analysis, we have observed that the basal steady-state levels of mRNA for cholesterol side-chain cleavage (P-450scc), 3 beta-HSD, P-450c21, P-450c17, and P-450c11 were in the same range in the two zones and an administration of ACTH caused, in both zona FG and zona RE, a two- to threefold decrease in P-450c17 and P-450c21 steady-state mRNA levels, whereas P-450c11, 3 beta-HSD, and P-450scc steady-state mRNA levels remained unchanged. Our data suggest the presence of some factor(s) capable of rapidly deactivating the steroidogenic enzymes in the zona RE.
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PMID:Studies of adrenal steroidogenic enzymes in guinea pigs. 131 81

In this paper we assess the qualitative and quantitative differences in adrenal function before and after adrenocorticotropic hormone (ACTH) stimulation between normal weight and overweight precocious pubarche (PP) patients. Twelve of the 22 PP patients had a normal body weight for height with linear growth and bone ages (BAs) that were appropriate for chronological age. The remaining 10 PP patients had body weights which were greater than 120% of ideal weight for height and body mass indices (BMIs), which were more than 125% of the ideal for age and sex. In six overweight patients, linear growth was accelerated and BAs were advanced beyond chronological age. All patients underwent an ACTH stimulation test where they received an intravenous bolus of 250 micrograms Cortrosyn. Blood samples were obtained at 0' and 60' for 17-OHProgesterone (17-OHP), 17-OHPregnenolone (17-OHPG), dehydroepiandrosterone (DHEA), androstenedione (A-dione), and cortisol levels. Results of the baseline and stimulated adrenal hormones in the normal weight children were found to be within reference range for normal Tanner I children. In contrast, two of the 10 overweight children were suspected of having congenital adrenal hyperplasia [one with 21-hydroxylase (21-OHase) deficiency, another with 3-betahydroxysteroid (3 beta ol) deficiency]. These two children were indistinguishable in their linear growth rate and degree of skeletal maturation from the other overweight children. In both patients the BA/chronological age and BA/height age (HA) ratios were within two standard deviations of the mean for the overweight patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excess weight and precocious pubarche in children: alterations of the adrenocortical hormones. 165 53

The long-term effects of angiotensin-II (A-II) and corticotropin (ACTH) on bovine adrenal fasciculata cells (BAC) were studied. Cells were pretreated for 3 days with either A-II or ACTH followed by an examination of the acute steroidogenic response to both hormones as well as the ability to convert several steroid precursors to cortisol and corticosterone. ACTH pretreatment caused a marked increase in cortisol output associated with a decrease in corticosterone secretion in response to both hormones leading to a 50-fold decrease in the corticosterone/cortisol ratio compared to control cells. After incubation with saturating concentrations (5 X 10(-5) M) of 22 R-hydroxycholesterol, pregnenolone or progesterone, ACTH-pretreated cells produced more cortisol than corticosterone whereas the contrary was observed in control cells. However, the conversion of 17 alpha-hydroxyprogesterone and 11-deoxycortisol to cortisol by ACTH-pretreated cells was lower than by control cells. Thus, the main effects of ACTH were a marked increase of 17 alpha-hydroxylase and a small but significant decrease of 21-hydroxylase and 11 beta-hydroxylase activities. A-II pretreatment produced, in a concentration-dependent manner, a down-regulation of its own receptors and homologous and heterologous steroidogenic desensitization. At maximal concentrations (10(-6) M) A-II reduced by 70% its own receptors while the steroidogenic response to A-II and ACTH was reduced by 95% and 75%, respectively. However, the coupling of A-II receptors to phosphoinositide pathway and to Ca2+ influx, as well as its potentiation effect on ACTH-induced cAMP production were similar in control and A-II pretreated cells. Moreover, the conversion of several steroid precursors to corticosterone was similar in control cells and A-II-pretreated cells, whereas the conversion to cortisol was reduced by approximately 30% due mainly to a decrease of 17 alpha-hydroxylase activity. Thus, the marked steroidogenic desensitization induced by A-II is most likely related to some alteration located beyond the activation of the two branches of the phosphoinositide pathway and before the first steps of steroidogenesis.
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PMID:Opposite effects of angiotensin-II and corticotropin on bovine adrenocortical cell steroidogenic responsiveness. 166 31

The steroid 21-hydroxylase (21-OHase) gene is selectively expressed at high levels in cells of the adrenal cortex and is transcriptionally regulated by corticotropin (ACTH). In this study, we examined the contribution of cis-acting nucleotide sequences to the regulated expression of the mouse 21-OHase gene. The 5'-flanking sequences of the mouse 21-OHase gene, extending 330 bp upstream from the transcription initiation site, were placed in front of the human growth hormone (hGH) reporter gene, and expression of the fusion gene was measured following transient transfection in Y1 mouse adrenocortical tumor cells. The 330 bp of 21-OHase flanking sequence directed both basal and ACTH-stimulated expression of hGH in Y1 adrenocortical cells but did not direct hGH expression in I-10 mouse testicular Leydig cells or in mouse fibroblast L cells. The 21-OHase/hGH fusion gene was poorly expressed in Y1 mutants defective in cAMP-dependent protein kinase activity. These results indicate that sequences necessary for adrenal cell-selective and ACTH-regulated expression of the 21-OHase gene reside within the first 330 bp of 5'-flanking DNA and that constitutive expression of the gene requires the integrity of cAMP-dependent protein kinase. The constitutive expression of hGH in Y1 cells was decreased dramatically (40-fold) when the 21-OHase flanking sequences in front of hGH were shortened to 156 bp from the transcription initiation site and was restored when the upstream sequences of the 21-OHase gene, from -330 to -150, were added back; the sequences from -330 to -150 were equally effective in either the correct or reverse orientation. From these observations, we conclude that an enhancer element is contained within the sequences from -330 to -150 bp upstream of the 21-OHase transcription initiation site.
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PMID:An enhancer element and a functional cyclic AMP-dependent protein kinase are required for expression of adrenocortical 21-hydroxylase. 284 6

The S region of the murine major histocompatibility complex contains two structurally related genes (21-OHase A and 21-OHase B) that encode 21-hydroxylase (21-OHase), an enzyme essential for the synthesis of adrenal steroids. Expression of these two genes has been analyzed by using oligonucleotide probes specific for the 21-OHase A and B genes and by DNA-mediated gene transfer. Hybridization of the oligonucleotides to blots of BALB/c adrenal RNA demonstrated that all 21-OHase mRNA is derived from the 21-OHase A gene. Cosmids bearing either the 21-OHase A or B gene were introduced into Y1 adrenocortical tumor cells by cotransfection with pSV2-neo. Cells transfected with the 21-OHase A gene expressed 21-OHase as determined by steroid metabolism and by RNA blot hybridization; 21-OHase transcripts were not detected in parent Y1 cells or in cells transfected with the 21-OHase B gene. Treatment of 21-OHase A transfectants with adrenocorticotropin increased 21-OHase mRNA levels by up to 10-fold, thus mimicking the observed effect of this hormone on 21-OHase levels in primary adrenal cultures. The regulated expression of the 21-OHase A gene in transfected Y1 cells should provide a useful system for the investigation of factors controlling the adrenal-specific regulation of 21-OHase activity.
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PMID:Expression of murine 21-hydroxylase in mouse adrenal glands and in transfected Y1 adrenocortical tumor cells. 299 80

The developmental expression of adrenocortical steroid hydroxylases was studied in bovine fetuses from 40 to 280 days gestational age. The expression of P-450(17 alpha) is first detected at a gestational age of 50 days and reaches a maximum at 60-70 days. The expression of P-450(17 alpha) then declines and is nondetectable at a gestational age of 100 days. P-450(17 alpha) is not expressed again until about 240 days, i.e. shortly before birth (approximately 280 days). P-450scc, P-450c21, P-450(11 beta) and adrenodoxin were present in fetal adrenals throughout gestation. This "on-off-on" pattern of P-450(17 alpha) expression during fetal development was associated with a corresponding episodic production of cortisol. Immunoreactive corticotropin (ACTH) levels in fetal plasma were elevated in small fetuses (corresponding to less than or equal to 100 days) and in near-term fetuses (corresponding to greater than 250 days) compared with those in mid-gestation fetuses. In primary culture, adrenal cells from mid-gestation fetuses contained no detectable P-450(17 alpha) but rapidly responded to ACTH with an increase in P-450(17 alpha) protein and mRNA. The tissue specificity of the developmental patterns is emphasized by the fact that both P-450(17 alpha) and P-450scc were detectable throughout the development of the fetal testes, whereas only P-450scc was detectable in fetal bovine ovary prior to 200 days. Thus, in fetal bovine adrenal it appears that ACTH is the major regulatory factor effecting the intermittent presence of P-450(17 alpha), whereas the presence of the other steroid hydroxylases is either regulated by additional factors or shows a much different sensitivity to ACTH.
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PMID:Developmental expression of bovine adrenocortical steroid hydroxylases. Regulation of P-450(17 alpha) expression leads to episodic fetal cortisol production. 326 67

The early events of steroidogenesis, following adrenocorticotropin (ACTH) stimulation, were investigated in primary cultures of bovine adrenal cortical cells. Steroidogenesis was elevated 4-fold within 5 min of exposure to 10(-7) M ACTH and increased linearly for 12 h and declined thereafter. Cholesterol side-chain cleavage (SCC) activity was increased 2.5-fold in mitochondria isolated from cells exposed for 2 h to ACTH and 0.5 mM aminoglutethimide, even though cytochrome P-450scc only increases after 12 h. Mitochondrial free cholesterol levels increased during the same time period (16.5 to 25 micrograms/mg of protein), but then both cholesterol levels and SCC activity declined in parallel. It is concluded that early ACTH-induced effects on cellular steroidogenesis result from these changes in mitochondrial free cholesterol. The maximum rate of cholesterol transport to mitochondria in aminoglutethimide-blocked cells (8.6 micrograms/mg of protein/h) was consistent with both the maximum rate of mitochondrial cholesterol SCC and cellular steroidogenesis (6.0 micrograms of pregnenolone/mg/h and 5.5 micrograms of steroid/mg of mitochondria/h, respectively). Cycloheximide (0.2 mM) rapidly blocked (less than 10 min) cellular steroidogenesis, cholesterol SCC activity, and access of cholesterol to cytochrome P-450scc without affecting mitochondrial free cholesterol. The distribution of steroid products fell into three distinct phases during a 24-h period following ACTH stimulation: an initial increase in SCC activity (0-4 h), elevation of androstenedione in place of corticosterone (4-12 h), and then in place of cortisol (12-24 h). The changes from 4 to 24 h result from a progressive stimulation by ACTH of 17 alpha-hydroxylase activity (but not 21-hydroxylase or C17:20 lyase activities) that is maintained even when stimulation of total steroidogenesis has stopped.
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PMID:Characterization of the acute stimulation of steroidogenesis in primary bovine adrenal cortical cell cultures. 608 83

The action of adrenocorticotropin (ACTH) to stimulate synthesis of steroid 21-hydroxylase was studied in bovine adrenocortical cells maintained in primary culture. Continuous treatment with ACTH (1 microM) caused an increased incorporation of [35S]methionine into cytochrome P-450C21 (21-hydroxylase cytochrome P-450); a maximum value (15-fold increase) was attained 24 h after initiation of ACTH treatment. Also, a 3-fold increase in cytochrome P-450C21 synthesis was observed in a cell-free translation system programmed by RNA isolated from cells that were exposed to ACTH for 24 h. The rate of synthesis of cytochrome P-450C21 declined after longer periods of treatment of the cells with ACTH. The increase in synthesis of cytochrome P-450C21 was associated with an increase (3-6 fold) in both total cytochrome P-450 content and in the type I absorbance change induced by 17 alpha-hydroxyprogesterone in microsomes prepared from ACTH-treated cells, as compared with that in microsomes from control cells. By contrast, ACTH did not act to increase steroid 21-hydroxylase activity in cultured intact cells, as determined by the rate of secretion of cortisol and 11-deoxycortisol, after addition of 17 alpha-hydroxyprogesterone to the medium. Similarly, there was no difference in steroid 21-hydroxylase activity in postmitochondrial supernatant fractions prepared from non-treated or ACTH-treated cells. Cytochrome P-450C21 was found to be synthesized as a form identical in molecular weight to the mature form. These results are indicative that ACTH acts to stimulate the synthesis of steroid 21-hydroxylase, yet is without a demonstrable effect on the activity of this enzyme which is high throughout the time period of the experiment.
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PMID:Effect of adrenocorticotropin on steroid 21-hydroxylase synthesis and activity in cultured bovine adrenocortical cells. Increased synthesis in the absence of increased activity. 630 8

The immediate-early gene NGFI-B encodes an orphan nuclear receptor that binds DNA as a monomer and activates transcription through a canonical response element (NBRE). NGFI-B is expressed under basal conditions and in response to external stimuli in many mammalian tissues. In particular, NGFI-B expression is dramatically elevated in the adrenal cortex in response to stress and in Y1 adrenocortical cells in response to adrenocorticotropin. NGFI-B activates transcription through an NBRE of the gene encoding 21-hydroxylase (P450c21) in Y1 cells. Steroidogenic factor 1 (SF-1), a homolog of NGFI-B, also activates the P450c21 promoter. To examine the influence of these factors on P450c21 expression in vivo and the function of the hypothalamic-pituitary-adrenocortical axis as a whole, we generated NGFI-B (-/-) mice. These mice thrive and reproduce normally and maintain normal basal adrenocorticotropin, corticosterone, and P450c21 mRNA levels. In response to increases in adrenocorticotropin, NGFI-B (-/-) and wild-type mice demonstrated equivalent increases in serum corticosterone levels. Furthermore, and in contrast to in vitro results, no increases in P450c21 mRNA levels were observed in response to increases in adrenocorticotropin in NGFI-B (-/-) or wild-type mice. While SF-1 mRNA levels were not increased with increased steroidogenic demand, adrenal expression of Nurr1, a close homolog of NGFI-B, was induced to a greater extent by lipopolysaccharide in NGFI-B (-/-) mice than in wild-type mice. Finally, when the administration of dexamethasone for suppression was stopped, P450c21 mRNA and serum corticosterone levels recovered at the same rate in wild-type and NGFI-B (-/-) mice. Thus, while NGFI-B appears poised to affect the structure and function of the adrenal gland, the gland functions normally in its absence, suggesting that other factors, including Nurr1 and SF-1, are sufficient to drive P450c21 expression in mice and maintain normal steroidogenesis.
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PMID:Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. 762 27


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