Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional development of the neonatal rat adrenal cortex is characterized by a triphasic response to adrenocorticotropic hormone (ACTH), with a nadir in responsiveness around neonatal day 10 (d10). In this study, the hypothesis was tested that hyporesponsiveness to ACTH partly results from deficiencies in steroidogenic enzyme content. Immunoreactive (ir) levels of mitochondrial cytochrome P450 enzymes (side chain cleavage (P450scc) and 11 beta-hydroxylase (P450c11)) did not change during neonatal development. Immunoreactive levels of microsomal 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), however, were significantly and comparably lower in both day 1 (d1) and d10 neonates compared to adult rats. Activity of 3 beta-HSD did not parallel changes in ir 3 beta-HSD content. Enzyme activity was low on d1 (approximately 39% of adult activity), but by d10 was statistically equivalent to that of microsomes from adult adrenal glands. Immunoreactive levels of microsomal cytochrome P450 21 alpha-hydroxylase (P450c21) were significantly lower in d1 glands than in adult glands (by approximately 50%), but by d10 were statistically indistinguishable from adults. On the other hand, P450c21 activity was equivalent on d1 and d10 and both were significantly lower compared to adults (approximately 62% of adult activity). ACTH injections from d3-d10 facilitated the adrenocortical steroidogenic response to ACTH on d10. This treatment increased levels of ir 3 beta-HSD, but not ir P450c21. The results suggest that rat adrenocortical 3 beta-HSD and P450c21 are developmentally and differentially regulated, and that ir levels of the proteins are not correlated with enzyme activity during the neonatal period. One possible explanation for these observations is that multiple isoforms of the two enzymes, with different antigenic and enzymatic properties, may be expressed during development at different times. In addition, the combined decreased activities of these two enzymes can almost entirely account for the decreased steroidogenic output of rat adrenocortical cells on d1, but not during the later neonatal period.
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PMID:Ontogeny of immunoreactive and bioactive microsomal steroidogenic enzymes during adrenocortical development in rats. 867 48

Using cultured bovine adrenal fasciculata cells (BAC), we investigated the effects of two hormones, corticotropin (ACTH) and angiotensin II (Ang-II) and two growth factors, insulin-like growth factors I (IGF-I) and transforming growth factor beta 1 (TGF beta 1), on the mRNA levels of nuclear proto-oncogenes of the Fos and Jun families and on the mRNA levels of genes expressed in BAC coding for ACTH and AT1 receptors, cytochrome P450scc and P450 17 alpha and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). ACTH and IGF-1 increased c-fos and jun-B mRNA levels early with later increases in the levels of mRNA for the ACTH receptor and the three steroidogenic enzymes, and enhanced steroidogenic responses to both ACTH and Ang-II. In contrast, Ang-II increased mRNA coding for the three proto-oncogenes (cfos, c-jun, and jun-B), decreased those for P450 17 alpha and 3 beta-HSD, and caused marked homologous and heterologous steroidogenic desensitization. TGF beta 1 increased only jun-B mRNA and markedly reduced BAC-differentiated functions and steroidogenic responsiveness to both ACTH and Ang-II. The long-term effects of ACTH on human adrenal fasciculata cells were comparable with those observed in BAC, whereas the long term effects of Ang-II and TGF beta 1 were different from those observed in BAC. Whether these species-specific differences are related to a different effect of these factors on proto-oncogene expression is not yet known.
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PMID:Regulation of primary response and specific genes in adrenal cells by peptide hormones and growth factors. 873 96

In this review we analyze the morphologic changes, hypothalamic-pituitary-adrenal (HPA) axis functions, glucocorticoid (GC) receptors, and steroidogenic enzyme activities in both animals and humans during aging. In rodent studies, older animals tend to show: 1) hypertrophy of adrenal zona fasciculata (ZF) cells; 2) neuronal loss in the hypothalamic area; 3) loss of GC receptors in the hippocampus; 4) raised circulating adrenocorticotropic hormone (ACTH) and GC levels, and increased release of corticotropin-releasing hormone from the hypothalamus; 5) reduced suppression of endogenous GC secretion after administration of dexamethasone; 6) decreased attenuation of response to chronic stress; and 7) increased activity of P450scc and 21-hydroxylase. According to the GC cascade hypothesis, stress and GCs facilitate the aging process in rats. Stress induces downregulation of GC receptors in the hippocampus, then impairs GC feedback on stress-induced HPA axis activation. Finally, an increase in the basal level of corticosterone and extended GC secretion following stress occurs. Because activation of the hippocampus decreases HPA axis function, the unrestrained elevation of GC concentration and the reduction in the level of GC receptors in the hippocampus may gradually weaken the feedback mechanisms and halt the response to stress. In humans, there are conflicting reports of HPA axis function during aging, so it is difficult to make a final conclusion regarding the relationship between aging and HPA axis function.
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PMID:Glucocorticoids and aging. 934 78

A 48-year-old woman with Cushing's syndrome due to bilateral adrenocortical adenomas is reported. The patient presented with a typical Cushingoid appearance. The serum cortisol level was elevated with loss of the diurnal rhythm and the plasma adrenocorticotropic hormone (ACTH) level was undetectable. Dynamic testing showed no suppression of urinary 17-OHCS by high-dose dexamethasone and no stimulation by metyrapone. An abdominal computed tomography (CT) scan showed bilateral adrenal tumors. Bilateral adrenalectomy was performed. The right adrenal gland contained a tumor that was encapsulated and consisted mainly of compact cells. The surrounding cortex was atrophic. The left adrenal gland contained an encapsulated tumor composed predominantly of clear cells. There were numerous small adrenocortical nodules in the surrounding cortex. Immunohistochemical analysis of steroidogenic enzymes (P450scc, 3beta-HSD, P450c21, P450c17 and P450c11) was performed. Immunoreactivity of all the enzymes was intense in the compact cells of the right adrenocortical adenoma, while the adjacent non-neoplastic cortex was negative for the enzymes. In the left adrenal tumor, the immunoreactivity of 3beta-HSD was intense, while that of P450c17 was weak. In the adrenocortical nodules, 3beta-HSD activity was sporadically observed. G protein genes encoding Gs alpha and Gi2 were examined for activating mutations at codons 201 and 227 (Gs alpha) and codons 179 and 205 (Gi2 alpha) in the bilateral adrenal tumors, but no mutations were found. The bilateral adenomas of this patient showed marked differences in microscopic and immunohistochemical studies, suggesting that the capacity of steroidogenesis differs between the right and left tumors.
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PMID:Cushing's syndrome due to bilateral adrenocortical adenomas with different pathological features. 939 54

The steroidogenic acute regulatory protein (STAR) participates in steroidogenesis through the mitochondrial transfer of cholesterol to cytochrome P450scc. The rat adrenal Star gene is transcribed as a 3. 5-kilobase pair (kb) and 1.6-kb mRNA with the larger mRNA predominating ( approximately 85% of total) in vivo. Hypophysectomy (HPX) produced a 3-5-fold decrease in Star mRNA along with a loss of adrenal steroids, whereas P450scc mRNA decreased by less than 2-fold. Adrenocorticotropic hormone (ACTH) treatment of HPX rats maximally stimulated steroidogenesis rates within 5 min with over 10-fold elevation of steady state blood levels occurring within 10 min. For intact rats there was a 5-10-fold larger increase, paralleling previously observed elevations of cholesterol-cytochrome P450scc association and metabolism in subsequently isolated adrenal mitochondria. ACTH did not increase either total STAR protein or a group of modified forms until at least 30 min after completion of acute stimulation, indicating that elevated translation of STAR protein cannot alone mediate this acute stimulation. Parallel slow changes in STAR protein and corticosterone formation after ACTH treatment are consistent with participation of STAR forms as co-regulators of these hormonal responses. ACTH stimulation of HPX rats increased Star mRNA by 2.5-fold within 20 min and by 4.5-fold after 1 h, thus preceding the rise in the STAR protein. A 3.5-kb Star cDNA clone isolated from a rat adrenal cDNA library exhibited a 0.9-kb open reading frame and a 2.5-kb 3'-untranslated region (3'-UTR). The open reading frame sequence differed at only 12 amino acids from that of the mouse Star. The rat Star gene seven exons with exon 7 encoding the entire 2.5 kb of 3'-UTR of the 3.5-kb mRNA. The 3'-UTR sequence suggests that 1.6- and 3.5-kb mRNA are formed by an alternative usage of different polyadenylation signals. Multiple UUAUUUA(U/A)(U/A) motifs also suggest additional regulation through this extended 3'-UTR. Although elevation of STAR protein by ACTH does not cause the acute increase in adrenal cholesterol metabolism, changes in the turnover or distribution of an active STAR subfraction cannot be excluded.
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PMID:Characterization of the rat Star gene that encodes the predominant 3.5-kilobase pair mRNA. ACTH stimulation of adrenal steroids in vivo precedes elevation of Star mRNA and protein. 951 65

Stress susceptibility in pigs is inherited by a single recessive gene (Hal(n)), and homozygous individuals can be identified by exposure to halothane anesthesia. Previous studies have shown that in stress-susceptible pigs, exposure to a high ambient temperature resulted in a twofold increase in corticotropin (ACTH) and lower plasma cortisol. To determine whether there is a fundamental difference in adrenocortical function between halothane-sensitive (HAL-S) and halothane-resistant (HAL-R) pigs, independent of other factors influencing the hypothalamic-pituitary-adrenal (HPA) axis, we compared cortisol responses to ACTH and 8-bromo-cyclic AMP (8-Br-cAMP) in HAL-S and HAL-R pig adrenocortical cells in vitro. We also determined directly the accumulation of four different mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450(scc)), 17alpha-hydroxylase cytochrome P450 (P450(17alpha)), 21-hydroxylase cytochrome P450 (P450(c21)) and 11beta-hydroxylase cytochrome P450 (P450(11beta)) in HAL-S pig adrenal cells and compared them to HAL-R pigs. A time- and dose-dependent increase in medium content of cortisol and cAMP was observed after ACTH treatment. 8-Br-cAMP also caused a time- and dose-dependent increase in cortisol production in the medium. Addition of ACTH or 8-Br-cAMP to HAL-S and HAL-R male Lanyu small-ear miniature pig adrenocortical cells increased cortisol production in a dose- and time-related manner. However, cells isolated from HAL-S pigs had a lower cortisol production in response to ACTH or 8-Br-cAMP compared to those from HAL-R pigs. Treatment of cultured cells with 8-Br-cAMP (0.5 mM) for 18 h resulted in a significant increase in P450(scc), P450(17alpha), P450(c21), and P450(11beta) mRNA levels. In the absence of 8-Br-cAMP, the four genes were expressed constitutively in both HAL-S and HAL-R pig adrenal cells. Densitometric scanning of the autoradiograph indicated that the relative amounts of P450(scc) and P450(17(alpha)) mRNAs in HAL-S pig adrenal cells were between 48% and 53% of those detected in HAL-R pig adrenal cells (P < 0.05). No difference in the amounts of P450(c21) and P450(11beta) was seen in HAL-S and HAL-R pig adrenal cells. Addition of 8-Br-cAMP (0.5 mM) resulted in a uniform increase in the levels of all four P450 mRNAs in both HAL-S and HAL-R pig adrenal cells. However, the amounts of P450(scc) mRNA in HAL-S pig adrenal cells were 67% (P < 0.05) of those measured in HAL-R pig adrenal cells, whereas the amounts of P450(17alpha ), P450(c21), and P450(11beta) mRNAs were similar in these cells. Our data suggest an HPA axis defect in HAL-S pigs at the adrenal level. This defect appears to be at the level of P450scc gene expression, which could be partially related to reduced cortisol production by ACTH stimulation.
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PMID:Expression of steroidogenic enzyme messenger ribonucleic acid and cortisol production in adrenocortical cells isolated from halothane-sensitive and halothane-resistant pigs. 1090 55

The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in
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PMID:Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. 1110 74

Real-time fluorescence analysis revealed that the activity of cytochrome P450scc was related to Ca2+ signals arising from extracellular NADPH, ACTH and ATP stimulation in adrenocortical fasciculata cells. The side-chain cleavage reaction by cytochrome P450scc was measured with 3beta-hydroxy-22,23-bisnor-5-cholenyl ether (cholesterol-resorufin) by observing the distinct increase in fluorescence upon conversion of cholesterol-resorufin to resorufin and pregnenolone. Adrenocorticotropic hormone (ACTH) induced a relatively small stimulation of the P450scc activity. A significant production of resorufin was revealed after stimulation of cell cultures with 100 pM, 1 nM of ACTH for 3 h. On the other hand, extracellular NADPH was found to rapidly and greatly stimulate the resorufin production in intact cells immediately after the addition of 50-500 microM NADPH. The extracellular NADPH stimulation was prevented by the addition of thapsigargin and EGTA which abolished Ca2+ oscillations induced by NADPH. Suramin, a specific antagonist of the P2y type ATP receptor, also completely abolished the NADPH-induced cholesterol-resorufin conversion. These results imply that extracellular NADPH (membrane impermeable) produced Ca2+ oscillations through its binding to ATP receptor thereby stimulating the activity of P450scc. The application of 45-500 microM extracellular ATP to cells did not, however, significantly increase the resorufin production. These three stimulators produced very different types of Ca2+ signals. ACTH induced mainly a series of Ca2+ spikes superimposed on a long-lasting basal Ca2+ elevation. The Ca2+ signals induced by NADPH showed predominantly a series of Ca2+ spikes without elevation of the basal Ca2+ concentration. Only long-lasting Ca2+ elevation was induced by extracellular ATP. The stimulation of cytochrome P450scc may thus be correlated with the different patterns of Ca2+ signals.
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PMID:Real-time fluorescence analysis on molecular mechanisms for regulation of cytochrome P450scc activity upon steroidogenic stimulation in adrenocortical cells. 1113 24

We have demonstrated previously that plasma adrenocorticotropin hormone and cortisol responses to exogenous and endogenous stimuli are reduced in fetuses of mildly undernourished ewes. In the present study, we examined the molecular regulation of fetal hypothalamic-pituitary-adrenal (HPA) axis function at 127-130 days gestation (dGA) following 15% reduction in maternal nutrition between 0 and 70 dGA. Using in situ hybridization, we found that corticotropin releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) was lower in fetuses from nutrient restricted ewes than in controls. Restricted fetuses also had greater levels of mRNA encoding preproenkephalin (PENK) and magnocellular arginine vasopressin (AVP) in the PVN. Expression of oxytocin mRNA and parvocellular AVP mRNA in the PVN and pro-opiomelanocortin mRNA in the pituitary were unchanged. Glucocorticoid receptor mRNA expression was unaltered at the PVN, but was reduced (> 40%) in the anterior pituitary of restricted fetuses. Northern blot analysis demonstrated that levels of adrenal P450scc mRNA and P450(C17) mRNA were not different between the groups. We conclude that the reduction in HPA function reported previously is mediated, at least in part, by a decrease in expression of CRH mRNA and increase in PENK mRNA in the PVN.
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PMID:Maternal undernutrition in early gestation alters molecular regulation of the hypothalamic-pituitary-adrenal axis in the ovine fetus. 1167 54

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase.
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PMID:Effects of S-petasin on corticosterone release in rats. 1281 4


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