Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q7LGC8 (HSD)
 3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, progesterone was found to regulate the initiation and biosynthetic rate of myelin synthesis in Schwann cell/neuronal cocultures. The mRNA for cytochrome P450scc (converts cholesterol to pregnenolone), 3beta-hydroxysteroid dehydrogenase (3beta-HSD, converts pregnenolone to progesterone), and the progesterone receptor were found to be markedly induced during active myelin synthesis. However, the cells in the cocultures responsible for these changes were not identified. In this study, in situ hybridization was used to determine the localization of the enzymes responsible for steroid biosynthesis. The mRNA for cytochrome P450scc and 3beta-HSD were detected only in actively myelinating cocultures and were localized exclusively in the Schwann cells. Using immunocytochemistry, with minimal staining of the Schwann cells, we found the progesterone receptor in the dorsal root ganglia (DRG) neurons. The progesterone receptor in the neurons translocated into the nuclei of these cells when progesterone was added to neuronal cultures or during myelin synthesis in the cocultures. Additionally, a marked induction of the progesterone receptor was found in neuronal cultures after the addition of progesterone. The induction of various genes in the neurons was also investigated using mRNA differential display PCR in an attempt to elucidate the mechanism of steroid action on myelin synthesis. Two novel genes were induced in neuronal cultures by progesterone. These genes, along with the progesterone receptor, were also induced in cocultures during myelin synthesis, and their induction was blocked by RU-486 (a progesterone receptor antagonist). These genes were not induced in Schwann cells cultured alone after the addition of progesterone. These results suggest that progesterone is synthesized in Schwann cells and that it can indirectly regulate myelin formation by activating transcription via the classical steroid receptor in the DRG neurons.
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PMID:Progesterone synthesized by Schwann cells during myelin formation regulates neuronal gene expression. 1088 68

We review various theories of the pathogenetic mechanisms of steroid-induced and essential hypertension. We investigated the possibility that a pathogenetic mechanism leading to glucocorticoid (GC)-induced hypertension or to mineralocorticoid (MC)-induced hypertension, or both, may be of critical importance in primary hypertension. We studied plasma levels of corticosterone (BK) and aldosterone (Aldo), and their concentrations in arterial and renal tissues of spontaneously hypertensive rats (SHR), a model of primary hypertension, and in the antecedent strain WKY rats as a normotensive control. Plasma levels of BK and Aldo were found to be normal and identical in SHRs and WKYs. Tissue (intracellular) levels of BK were more than double in SHRs than in WKYs. Subsequently we examined the activity of 11 beta-hydroxy steroid dehydrogenase (11-HSD) in both aortic and renal tissues of SHRs and WKYs. 11-HSD converts BK to the corresponding 11-keto compound, 11-dehydro-corticosterone (cpd.AK), which is inactive, in view of its inability to bind to the MC receptors (and also to the GC receptors). BK, the main glucocorticoid in the rat, as well as cortisol, have high affinity for the MC-receptor (MR). Normally BK or cortisol are present in 10(2)-10(3) times greater concentrations than Aldo in tissues possessing MR. The enzyme 11-HSD deactivates BK (or cortisol), thus protecting MC-receptors in the MC target tissues from being activated by GC. When we examined arterial and renal tissue activities of 11-HSD in SHRs, the activity of 11-HSD was only one-third that found in the WKY rats. This explained higher levels of BK in the tissues of SHR, and suggested that decreased activity of 11-HSD is a pathogenetic factor for hypertension in SHRs. Thus, in a model of primary hypertension such as SHR, decreased activity of 11-HSD in the target tissues of MC appears to lead to glucocorticoid-induced mineralocorticoid hypertension.
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PMID:[Mechanism of primary hypertension]. 1090 53

Gap junctions are intercellular protein channels which provide a pathway for the exchange of ions and small molecules. This exchange of materials allows metabolic coupling of cells. Gap junction channels are made up of connexins, integral membrane proteins encoded by a multigene family. Rat testes contain mRNAs for at least five different connexins: Cx26, Cx32, Cx33, Cx37 and Cx43. Immunocytochemical studies have shown that Cx43 assembles gap junctions between Leydig cells. The present study investigated the expression and regulation of the Cx43 gene in rat Leydig cells. Purified Leydig cells were obtained from 40- to 80-day-old Sprague-Dawley rats using a combination of arterial perfusion, collagenase digestion, centrifugal elutriation and Percoll gradient centrifugation. Leydig cells from 20- and 30-day-old rats were isolated without arterial perfusion or centrifugal elutriation. Cx43 mRNA was present in 20-day-old rat Leydig cells, reached a plateau at day 40, and remained at high levels in 65- and 80-day-old rat Leydig cells. To evaluate the regulation of Cx43 gene expression, Leydig cells were cultured overnight and then treated with human chorionic gonadotropin (hCG) for variable periods of time. Addition of hCG (10 ng/ml) increased cytochrome P450 side-chain cleavage and steroidogenic acute regulatory protein mRNA levels and testosterone formation. However, Cx43 mRNA levels were inhibited by hCG in a time- and dose-dependent manner. Cx43 mRNA levels decreased 27% as early as 2 h after the addition of hCG and decreased 60% by 24 h. Treatment of Leydig cells with 8-bromo-cAMP (0.1 mM) for 6 and 24 h also reduced Cx43 mRNA levels by 36 and 56% respectively. Primary cultured Leydig cells stained strongly positive with anti-Cx43 monoclonal antibody. Treatment with hCG for 24 h reduced Cx43 signals and caused Cx43 to redistribute to the periphery of the cells. To evaluate the regulation of Cx43 in vivo, rats were treated with hCG (300 ng i.p.) and testes were removed 24 h later. Frozen section of testes revealed that these interstitial cells stained positive for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) by histochemical staining and were positive for Cx43 by immunofluorescence staining. The adjacent seminiferous tubules stained only weakly positive for Cx43. Twenty-four hours after hCG treatment, 3beta-HSD activity increased while Cx43 immunostaining of Leydig cells was reduced. In conclusion, gap junction channels of Leydig cells are regulated by hCG both in vivo and in vitro. hCG increased Leydig cell steroidogenesis and steroidogenic enzyme mRNA levels but caused a redistribution of Cx43.
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PMID:Expression and regulation of connexin43 in rat Leydig cells. 1092 34

Leydig cells in the adult rat testis differentiate during the neonatal-prepubertal period. However, the stimulus for the initiation of their differentiation is still not clear. In the present study our objectives were to test the effects of thyroid hormone and LH on the initiation of precursor cell differentiation into Leydig cells in the prepubertal rat testis. Four groups of Sprague-Dawley rats were used. All treatments began at postnatal Day 1. Rats in groups I, II, and III received daily s.c. injections of saline (200 microl, controls), triiodothyronine (T(3), 50 microg/kg body weight, hyperthyroid), and LH (ovine LH 10 microg/rat/day), respectively. Rats in group IV were made hypothyroid from postnatal Day 1 by adding 0.1% propylthiouracil (PTU) to their mother's drinking water. Testes of rats were collected at 7, 8, 9, 10, 11, 12, 16, and 21 days of age, fixed in Bouin's solution, and embedded in paraffin for immunocytochemical studies. Immunoexpression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and LH receptors (LHR) in testicular interstitial cells (other than the fetal Leydig cells) was observed using the avidin-biotin method. In control rats, out of all spindle-shaped cell types in the testis interstitium, only the peritubular mesenchymal cells showed positive immunolabeling for 3beta-HSD, beginning from the postnatal Day 11. However, positive immunolabeling for LHR was first detected in these cells at Day 12, i.e., after acquiring the steroidogenic enzyme activity. In T(3)-treated rats 3beta-HSD positive spindle-shaped cells were first observed at Day 9 (i.e., 2 days earlier than controls), and LHR-positive cells were first observed on Day 11 (2 days later than obtaining 3beta-HSD immunoactivity); they were exclusively the peritubular mesenchymal cells. The 3beta-HSD- and LHR-positive spindle-shaped cells were absent in the testis interstitium of LH-injected rats from Days 7 through 12 but were present at postnatal Day 16. In addition, more fetal Leydig cell clusters and fetal Leydig cells in mitosis were present in LH-treated rats compared to rats in all other treatment groups. Following their first detection, the number of positive cells for each protein continued to increase at each subsequent age in controls, T(3)-, and LH-injected groups. In PTU rats, 3beta-HSD and LHR-positive spindle-shaped cells were absent throughout the experimental period. From these observations, it is possible to suggest the following regarding the developing rat testis interstitium. 1) The precursor cells for the adult generation of Leydig cells in the postnatal rat testis are the peritubular mesenchymal cells. 2) Luteinizing hormone does not initiate the onset of mesenchymal cell differentiation into Leydig cells, instead it delays this process. However, daily LH treatment causes mitosis in fetal Leydig cells and increase in fetal Leydig cell clusters. 3) Thyroid hormone is critical to initiate the onset of mesenchymal cell differentiation into adult Leydig cells.
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PMID:Effects of thyroid and luteinizing hormones on the onset of precursor cell differentiation into leydig progenitor cells in the prepubertal rat testis. 1095 37

Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the gamma-aminobutyric acid type A (GABA(A)) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3beta-hydroxysteroid dehydrogenase (3beta-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABA(A) receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3beta-HSD-positive neurons also contain GABA(A) receptor alpha(3) and beta(2)/beta(3) subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxy-progesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABA(A) receptor agonist muscimol but was not affected by the GABA(B) receptor agonist baclofen. The selective GABA(A) receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABA(A) receptor alpha(3) and beta(2)/beta(3) subunits. Our data also demonstrate that GABA, acting on GABA(A) receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3beta-HSD and cytochrome P450(C17) (17alpha-hydroxylase).
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PMID:gamma-Aminobutyric acid, acting through gamma -aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus. 1108 16

1. We analysed the number and size of different ovarian cell subpopulations of newly-hatched chicks by ovarian cell suspension count and morphometric/stereological methods as well as delta5-3beta-hydroxysteroid dehydrogenase (delta5-3beta HSD) activity in these cells treated in vivo with LH during embryonic development. 2. Fertile White Leghorn eggs received 1 microg LH applied to the chorioallantoic membrane on days 13, 15, and 17 of incubation. All animals were killed within 24 h after hatching, the left ovary was dissected and processed. 3. The results indicate that the number of germ, pregranulosa, interstitial and undifferentiated cells was not affected by LH treatment. However, we observed an increase in the size of individual interstitial cells of the ovarian medulla. In these cells, delta5-3beta HSD activity was increased in response to LH. 4. These findings suggest that LH does not exert a proliferative effect on the cells of the prefollicular ovary of the chick and that interstitial cells can be target cells for LH, increasing their steroidogenic activity due to LH treatment.
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PMID:Effect of luteinising-hormone in vivo on ovarian cell subpopulations of newly-hatched chicks. 1112 92

The signal initiating ovarian theca cell (TC) differentiation is gonadotropin independent because theca precursor cells do not contain LH receptors. Previously we demonstrated that preantral follicles produce paracrine TC differentiating factors that promote androgen production by an LH-independent mechanism. This study tested the effects of two granulosa cell-produced peptides, insulin-like growth factor-I (IGF-I) and stem cell factor (SCF), on TC differentiation and androgen production. Neutralizing antibodies to either IGF-I or SCF blocked the stimulatory effects of follicle-conditioned medium on TC precursor differentiation more than 90%. The TC isolated from the ovaries of hypophysectomized immature rats by percoll gradient centrifugation were cultured (48 h) with and without SCF (0-100 ng/ml) and IGF-I (0-100 ng/ml) to test their effects on TC differentiation. Androsterone in the medium was measured by RIA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein (StAR), CYP11A, CYP17, and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) mRNAs were measured by specific reverse transcriptase polymerase chain reaction assays. Stem cell factor or IGF-I alone did not stimulate androsterone production but in combination caused a concentration-dependent increase in androsterone levels. Maximum androsterone levels were less than those stimulated by LH (0.1 ng/ml) alone. Although IGF-I synergistically augmented LH stimulation of androsterone production, SCF did not alter LH-stimulated androsterone production in the presence or absence of IGF-I. Stem cell factor alone had no effect on LH receptor, StAR, CYP11A, and 3beta-HSD mRNA expression but decreased CYP17 mRNA levels. Insulin-like growth factor-I alone had no effect on StAR or CYP17 mRNA expression but increased LH receptor, CYP11A, and 3beta-HSD mRNA levels. In combination, SCF plus IGF-I increased the expression of all five mRNAs. These data support the conclusion that IGF-I and SCF are important regulators of TC differentiation.
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PMID:Stem cell factor and insulin-like growth factor-I stimulate luteinizing hormone-independent differentiation of rat ovarian theca cells. 1115 46

The subcellular distribution of steroidogenic enzymes has so far been studied mostly in classical endocrine glands and in the placenta. In the peripheral intracrine organs which synthesize sex steroids there is no indication about the organelles which contain the enzymes involved in steroid biosynthesis. We have thus investigated the subcellular localization of two enzymes involved in the production of sex steroids, namely 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Using specific antibodies to these enzymes, we conducted immunoelectron microscopic studies in two peripheral tissues, namely the human prostate and mammary gland. In the prostate, immunolabelling for both 3beta-HSD and type 5 17beta-HSD was detected in the basal cells of the tube-alveoli as well as in fibroblasts and endothelial cells lining the blood vessels. In all the labelled cell types, the gold particles were distributed throughout the cytoplasm. No obvious association with any specific organelle could be observed, although some concentration of gold particles was occasionally found over bundles of microfilaments. In mammary gland sections immunolabelled for 3beta-HSD or type 5 17beta-HSD localization, labelling was observed in the cytoplasm of the secretory epithelial cells in both the acini and terminal ducts. Immunolabelling was also found in the endothelial cells as well as in fibroblasts in stroma and blood vessels. The gold particles were not detected over any organelles, except with the occasional accumulation of gold particles over microfilaments. The present data on the localization of two steroidogenic enzymes leading to the synthesis of testosterone indicate that these enzymes are located not only in epithelial cells but also in stromal and endothelial cells in both tissues studied. The absence of any association of the enzymes with membrane-bound organelles appears as a common finding in the reactive cell types of two peripheral tissues.
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PMID:Immunoelectron microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary gland. 1117 50

Classical 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) deficiency is a rare form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting from mutations in the HSD3B2 gene, causing varying degrees of salt-loss in both sexes and incomplete masculinization of the external genitalia in genetic males. To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing and 23 missense mutations) have been identified in the HSD3B2 gene. Results from functional charaterization studies of the mutant proteins agrees with the prediction that no functional type II 3beta-HSD isoenzyme is expressed in the adrenals and gonads of the patients with the severe salt-losing form, whereas the nonsalt-losing form causes an incomplete loss in enzymatic activity, thereby leaving sufficient enzymatic activity to prevent salt loss. Recent studies have highlighted the fact that various mutations appear to have a drastic effect upon the stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3beta-HSD deficiency. Finally, the functional characterization of the missense mutations known to be involved in this autosomal recessive disorder provides valuable information concerning the structure-function relationships of the 3beta-HSD enzyme superfamily.
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PMID:A new insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency. 1119 52

Lead is an environmental and occupational pollutant. It has been reported that lead affects the male reproductive system in humans and animals. However, the cellular mechanism of the adverse effect of lead on Leydig cell steroidogenesis remains unknown. To clarify whether lead has a direct effect on Leydig cells and how lead affects Leydig cells, MA-10 cells, a mouse Leydig tumor cell line, were exploited in this study. Lead acetate significantly inhibited hCG- and dbcAMP-stimulated progesterone production in MA-10 cells at 2 h. Steroid production stimulated by hCG or dbcAMP were reduced by lead. The mechanism of lead in reducing MA-10 cell steroidogenesis was further investigated. The expression of Steroidogenic Acute Regulatory (StAR) protein and the activities of P450 side-chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) enzymes were detected. Cells were treated with dbcAMP, 22R-hydroxycholesterol or pregnenolone alone or in combination with lead acetate ranging from 10(-8) to 10(-5) M for 2 h. The expression of StAR protein stimulated by dbcAMP was suppressed by lead at about 50%. Progesterone productions treated with 22R-hydroxycholesterol or pregnenolone were reduced 30-40% in lead-treated MA-10 cells. These data suggest that lead directly inhibited steroidogenesis by decreasing StAR protein expression and the activities of P450scc and 3beta-HSD enzymes with a dose-response trend in MA-10 cells. Moreover, cadmium, a calcium channel blocker, abolished inhibitory effect of lead on MA-10 cell steroid production. This indicates that lead might act on calcium channel to regulate MA-10 cell steroidogenesis.
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PMID:The inhibitory effects of lead on steroidogenesis in MA-10 mouse Leydig tumor cells. 1121 55


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