Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular effector systems which utilize PKA and PKC can be pharmacologically activated by forskolin and phorbol 12-myristate 13-acetate (PMA) and appear to be important for regulation of steroidogenesis by cells of the corpus luteum. In this study the effect of pharmacologic activation of PKA (forskolin) or PKC (PMA) on the activity of adenylate cyclase, cholesterol esterase, P450 cholesterol side chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5, delta 4 isomerase (3 beta HSD) was determined. Basal adenylate cyclase activity (as measured by intracellular and secreted cAMP) was extremely low in both large and small luteal cells. Forskolin stimulated adenylate cyclase activity in both large and small luteal cells but progesterone production was increased only in small cells. PMA inhibited progesterone production by large and forskolin-stimulated small cells without altering adenylate cyclase activity. Basal cholesterol esterase activity was greater in small than in large cells and was stimulated by forskolin only in small cells. PMA did not significantly alter cholesterol esterase activity in either cell type. Activity of P450scc or 3 beta HSD was measured by conversion of hydroxylated cholesterol derivatives (P450scc) or pregnenolone (3 beta HSD) to progesterone. Although basal progesterone production was 47 times greater in large than small cells, there was only 5.1 (P450scc) and 6.4 (3 beta HSD) times greater enzyme activity in large than in small luteal cells. Activation of PKA and/or PKC did not alter the activity of P450scc or 3 beta HSD in either cell type.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Steroidogenic enzyme activity after acute activation of protein kinase (PK) A and PKC in ovine small and large luteal cells. 814 91

We examined the regulation of steroid production in fetal zone cells from midgestation (16-21 weeks) human fetal adrenal glands to elucidate the mechanism by which these cells secrete large quantities of dehydroepiandrosterone sulfate (DHAS) and little cortisol in response to ACTH. Our underlying hypothesis is that estrogen and insulin-like to ACTH. Our underlying hypothesis is that estrogen and insulin-like growth factor-II (IGF-II) modulate the steroidogenic response of fetal zone cells to ACTH, driving steroid production toward DHAS rather than cortisol. We also hypothesize that the effects of IGF-II and estrogen on steroidogenesis are achieved by modulating the expression of key enzymes in the steroidogenic pathway. Basal cortisol secretion by cultured fetal zone cells was below the limit of assay sensitivity (< 0.54 pmol/10(5) cells.24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pmol/10(5) cells.24 h (mean +/- SE). ACTH-(1-24) increased the secretion of cortisol to 228.96 +/- 6.75 pmol/10(5) cells.24 h and that of DHAS to 2039.8 +/- 121.7 pmol/10(5) cells.24 h. Neither IGF-II nor estradiol (E2) affected basal (no added ACTH) steroid secretion by fetal zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secretion by fetal zone cells in a dose-dependent fashion. In contrast, E2 at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortisol production to basal levels, but increased ACTH-stimulated DHAS production 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mumol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- to 2-fold compared with control values. However, compared with cultures exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated cortisol secretion by about 60% and increased ACTH-stimulated DHAS secretion by about 50%. IGF-II increased the abundance of ACTH-stimulated mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha hydroxylase/17,20 lyase P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In addition, IGF-II increased the abundance of mRNA encoding P450c17 under basal conditions, but did not affect the basal expression of P450scc or 3 beta HSD. E2 had no effect on basal expression of these steroidogenic enzymes, but increased the abundance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abundance of mRNA encoding 3 beta HSD was not affected by E2. The effect of IGF-II and E2 in combination on steroidogenic enzyme mRNA abundance was not different from that of IGF-II alone. These data indicate that IGF-II increases ACTH-stimulated steroid production in fetal zone cells by increasing the expression of key steroidogenic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. 839 78

The postnatal differentiation of rat Leydig cells may be subdivided into three stages based on morphology and steroid production. The purpose of this study was to clarify the developmental mechanisms underlying increased testosterone production by measuring steady state levels of the mRNAs for three steroidogenic enzymes in isolated Leydig cells at each stage of differentiation. These include Leydig cell progenitors on day 21, immature Leydig cells on day 35, and adult Leydig cells on day 90. The steroidogenic enzymes were 1) cholesterol side-chain cleavage enzyme (CSCC), 2) 17 alpha-hydroxylase (P450-17 alpha), and 3) 3 alpha-hydroxysteroid dehydrogenase (3 alpha HSD). We report that levels of CSCC and P450-17 alpha mRNAs increase, whereas 3 alpha HSD mRNA levels decline during the course of Leydig cell differentiation. The levels of 3 alpha HSD mRNA were high in progenitor Leydig cells that appeared to contain little smooth endoplasmic reticulum and decreased in cells as smooth endoplasmic reticulum developed and other enzyme mRNAs increased. These observations suggest that the factors that regulate 3 alpha HSD mRNA levels are startlingly different from those that regulate the mRNA levels of CSCC and P450-17 alpha. We conclude that the progressive increase in the capacity of differentiating Leydig cells to produce testosterone can be explained in part by an increase in the activity of enzymes that synthesize testosterone (CSCC and P450-17 alpha) and a decrease in the activity of an enzyme that metabolizes testosterone and its precursors (3 alpha HSD).
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PMID:Differential regulation of steroidogenic enzymes during differentiation optimizes testosterone production by adult rat Leydig cells. 840 81

15-hydroxy prostaglandin dehydrogenase (PGDH) is the critical enzyme that determines metabolism of primary prostaglandins. Its expression is determined in part by steroid hormones, particularly progesterone, formed from delta(5) steroids through 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity. To assess whether the regulation of PGDH might occur in a paracrine, autocrine or intracrine fashion, we used immunohistochemistry (IHC) to determine the localisation of key steroidogenic enzymes in the equine placenta and compared these patterns to the distribution of immunoreactive (IR-) PGDH. Placental tissue was obtained from pony or Thoroughbred mares at about Days 150, 250-280 and >300 of pregnancy (term 320 to 360 days; n=5-8 each group). IR-PGDH, 3beta-HSD, cholesterol side chain cleavage enzyme (P450(scc)) and 17-hydroxylase/lyase (P450(C17)) were localised using specific antibodies and the avidin-biotin peroxidase technique and visualised using diaminobenzidine as substrate. IR-P450(scc) was present in trophoblast cells, but not in maternal tissues of the microcotyledons. In contrast, at Days 150 and 280, IR-PGDH was present in maternal epithelial and interstitial cells in the microcotyledons, but was not detected in trophoblast epithelium, chorioallantois or endometrial glands. After Day 300, IR-PGDH was present in the maternal epithelium and interstitial cells of the placenta and it was also present in trophoblast cells in some specimens.
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PMID:Localisation of 15-hydroxy prostaglandin dehydrogenase (PGDH) and steroidogenic enzymes in the equine placenta. 865 45

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NC), which is generated by nitrosation of nicotine, requires enzymatic activation by cytochrome-P450-mediated alpha-carbon hydroxylation to yield particularly powerful carcinogenic alkylating intermediates. Pyridine-N-oxidation and carbonyl reduction are detoxification pathways, the latter by providing the functional hydroxy moiety necessary for glucuronosylation and final excretion of NC. For more than a decade, the enzyme responsible for NC carbonyl reduction has awaited characterization. In the present study, we demonstrate that the NC carbonyl reductase is identical to 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the physiological function of which is the oxidoreduction of glucocorticoids. We conclude that the expression of 11 beta-HSD (together with glucuronosyl transferase) may have profound influence on the carcinogenic potency of NC and that many compounds of endogenous and exogenous origin, which are known to be substrates or inhibitors of 11 beta-HSD, may modulate NNK-induced carcinogenicity by competing for the same enzyme. In light of the known species and tissue differences in the expression of 11 beta-HSD isozymes, important aspects of NNK-induced tumorigenesis, such as metabolic activation versus inactivation or organospecificity, can now be re-evaluated.
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PMID:The identification of 11 beta-hydroxysteroid dehydrogenase as carbonyl reductase of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 868 62

The Leydig cell from the immature pig provides a good model for studying testicular steroidogenesis. Regulation of the enzymes involved, which has been well studied in rodents, has not been characterized in the pig. The objectives of this study were to examine the regulation of three steroidogenic enzymes in pig Leydig cells by LH/hCG and testosterone. The mRNA for P450 side-chain cleavage and P450(17) alpha-hydroxylase/C17-20-lyase, although constitutively expressed, decreased over time in culture, while that for 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) remained relatively constant. The mRNA for all three enzymes was increased in a dose- and time-dependent manner by treatment with hCG. Run-on experiments demonstrated that the main effect of the hormone was at the level of transcription. Treatment with hydroxyflutamide, either alone or in combination with hCG, had no effect on the mRNA for these enzymes. Treatment with hCG plus aminoglutethimide, an inhibitor of steroidogenesis, had no effect on the mRNA for the two P450 enzymes, but resulted in an increase in mRNA for 3 beta HSD when compared to treatment with hCG alone. However, exogenous testosterone could not block the effect of aminoglutethimide. Therefore, the steroidal regulation of 3 beta HSD in pig Leydig cells may act through a mechanism separate from the androgen receptor. While aspects of the regulation of these enzymes are similar to those seen in rodents, some significant differences exist. Our results support the concept that regulation of steroidogenic enzymes in Leydig cells is species-specific.
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PMID:Regulation by gonadotropins of the messenger ribonucleic acid for P450 side-chain cleavage, P450(17) alpha-hydroxylase/C17,20-lyase, and 3 beta-hydroxysteroid dehydrogenase in cultured pig Leydig cells. 882 39

Cortisol, produced by the primate fetal adrenal, regulates the maturation of organ systems necessary for extrauterine life. During most of primate pregnancy, however, the fetal adrenal lacks the enzyme 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), which is essential for cortisol synthesis. Therefore, we used immunohistochemistry and in situ hybridization techniques to investigate the developmental expression of 3 beta HSD in the fetal rhesus monkey adrenal from 109 days' gestation until term (165 +/- 5 days) and assessed the role of ACTH in the induction of its expression and localization. We also examined whether ACTH regulates the expression of two other steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage (P450scc) and P450 17 alpha-hydroxylase, 17/20-lyase (P450c17), in the fetal rhesus monkey adrenal. To stimulate ACTH secretion from the fetal pituitary in vivo, we administered metyrapone to late gestation fetal rhesus monkeys for 3-7 days. Adrenals were collected from untreated fetuses at 109-125 days (n = 5), 130-148 days (n = 7), 155-172 days (n = 4), and after metyrapone treatment at 135-137 days (n = 4). The cortical width and total amount of 3 beta HSD staining were measured using an image analysis system. 3 beta HSD was localized primarily in the definitive zone cells of the adrenal from fetuses between 109-148 days, whereas at term (155-172 days), 3 beta HSD was localized in both definitive and transitional zone cells. The cortical width and total amount of 3 beta HSD staining in the adrenal increased significantly (P < 0.05) between 148 days (137 +/- 14 microns and 3,689 +/- 522 grains) and 155 days (315 +/- 61 microns and 7,321 +/- 2,008 grains). Interestingly, in metyrapone-treated fetuses at 135-137 days, 3 beta HSD messenger RNA (mRNA) and protein were localized extensively in both the definitive and transitional zones, a pattern seen only in term fetal adrenals in untreated animals. In addition, metyrapone treatment significantly (P < 0.05) increased cortical width (386 +/- 95 microns) and total 3 beta HSD immunostaining (29,063 +/- 13,692 grains) compared with age-matched controls. In contrast to 3 beta HSD, P450scc mRNA was detected in the definitive, transitional, and fetal zones, and its expression was not altered after metyrapone treatment. P450c17 mRNA was detected in the transitional and fetal zones, and the relative abundance was greater in the transitional zone. The relative abundance of P450c17 mRNA was increased in the fetal zone after metyrapone treatment. In summary, at term or after metyrapone treatment, expression of 3 beta HSD is induced in the transitional zone of the fetal rhesus monkey adrenal gland, an indication of functional maturation of the primate adrenal cortex. These data suggest that the ontogenetic increase in fetal pituitary ACTH secretion plays an important role in the induction of 3 beta HSD expression in the transitional zone.
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PMID:Functional maturation of the primate fetal adrenal in vivo. II. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3 beta-hydroxysteroid dehydrogenase/isomerase. 889 68

Among the new antral follicles that develop after ovulation in pigs, the incidence of atresia, based on granulosa cell apoptosis, increases between Days 5 and 7 of the estrous cycle. The purpose of this study was to determine how follicular growth and atresia affected the expression of some key enzymes regulating follicular steroidogenesis and androgen receptor on Days 3, 5, and 7 after the onset of estrus. Ovaries were frozen in liquid propane for subsequent sectioning and immunohistochemical analysis. Ninety-six follicles were classified according to size as small (< 3 mm), medium (3-5 mm), or large (> 5 mm). Follicles in the active stages of the cell cycle were identified by the presence of the cell proliferation-associated nuclear antigen Ki-67 in granulosa cells. Follicles with apoptotic cells were identified by in situ 3'-end labeling of DNA. Staining intensity of antigens on sections was assigned a numeric value (0-3). Follicles assigned a value > 1 for 3'-end labeling in their granulosa cells were classified atretic. The percentage of atretic follicles increased (p < or = 0.05) from 5% on Days 3 and 5 to 41% on Day 7. Expression of Ki-67 in granulosa cells was more strongly (p < or = 0.05) associated with nonatretic follicles (98% expressing) than with atretic follicles (41% expressing). Aromatase cytochrome P450 (P450arom) was localized predominantly in granulosa cells of nonatretic follicles and was undetectable in atretic follicles. Androgen receptor in granulosa cells and expression of P450 17 alpha-hydroxylase/C17-20 lyase (P450c17) in theca interna were lower (p < or = 0.001) in atretic follicles than in nonatretic follicles. The expression of 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) was localized to the theca interna and was unaffected by follicle atresia. In nonatretic small follicles, the expression of P450arom and P450c17 decreased (p < 0.01) between Days 3 and 7 while expression of Ki-67 was unchanged. In nonatretic follicles, increased follicle size was associated with a decrease (p < 0.01) in androgen receptor expression and increases (p < 0.01) in P450arom, P450c17, and 3 beta HSD expression. In conclusion, increased expression of steroidogenic enzymes was associated with follicular growth. Loss of P450arom expression in vivo is an early event in atresia and is followed by decreased cell proliferation, and decreased expression of androgen receptor and P450c17.
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PMID:Expression of androgen receptors and steroidogenic enzymes in relation to follicular growth and atresia following ovulation in pigs. 890 4

Previous studies have shown that the ability of Brown Norway rat Leydig cells to produce testosterone declines significantly with age. To address the possible mechanism(s) by which aging Leydig cells lose steroidogenic function, we determined the effect of age on the steady-state levels of the mRNAs for the steroidogenic enzymes P450 cholesterol side-chain cleavage (P450scc), delta 5-3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), and 17 alpha-hydroxylase/C17-20 lyase (P450(17) alpha), and on the levels of immunoreactive steroidogenic enzyme proteins and enzyme activities. Northern blot analysis revealed that the levels of P450scc and P450(17) alpha mRNAs in Leydig cells isolated from the testes of aged (22-month-old) Brown Norway rats were reduced from their levels in young (4-month-old) rats, but that 3 beta-HSD mRNA was not reduced. Western blot analysis, however, revealed that cellular levels of each of the P450scc, P450(17) alpha, and 3 beta-HSD proteins were reduced with aging. The activities of the steroidogenic enzymes, assessed by incubating Leydig cells in culture with substrate and then summing all steroidogenic reaction products through testosterone, similarly revealed that P450scc, 3 beta-HSD, P450(17) alpha, and additionally 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), were all reduced with aging. We conclude that age-related loss of steroidogenic function results at least in part from reductions in the levels and activities of each of the steroidogenic enzymes responsible for converting cholesterol to testosterone, and not by differential regulation of these enzymes.
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PMID:Are Leydig cell steroidogenic enzymes differentially regulated with aging? 895 94

Steroidogenic factor-1/adrenal 4-binding protein (SF-1/Ad4BP) is an orphan nuclear receptor/transcription factor known to regulate the P450 steroid hydroxylases; however, mechanisms that regulate the activity of SF-1/Ad4BP are not well defined. In addition, little is known about the mechanisms that regulate the human steroidogenic enzyme, type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD II), the major gonadal and adrenal isoform. Regulation of the 3beta-HSD II promoter was examined using human adrenal cortical (H295R; steroidogenic) and cervical (HeLa; non-steroidogenic) carcinoma cells. H295R cells were transfected with a series of 5' deletions of 1251 base pairs (bp) of the 3beta-HSD II 5'-flanking region fused to a chloramphenicol acetyltransferase (CAT) reporter gene followed by treatment with or without phorbol ester (phorbol 12-myristate 13-acetate; PMA). CAT assay data indicated that the region from -101 to -52 bp of the promoter was required for PMA-induced expression. A putative SF-1/Ad4BP regulatory element, TCAAGGTAA, was identified by sequence homology at -64 to -56 bp of the promoter. Cotransfection of HeLa cells with the -101 3beta-HSD-CAT construct and an expression vector for SF-1/Ad4BP increased CAT activity 49-fold. Subsequent treatment with PMA induced an unexpected synergistic increase in transcriptional activity 540-fold over basal. Mutation of the putative response element (TCAAGGTAA to TCAATTTAA) abolished SF-1-induced CAT activity and the synergistic response to PMA. Gel mobility shift assays confirmed that SF-1/Ad4BP interacts with the putative element and transcripts for SF-1/Ad4BP were detected in H295R cells by Northern analysis. These data are the first to demonstrate 1) regulation of a non-cytochrome P450 steroidogenic enzyme promoter by SF-1/Ad4BP, 2) a powerful synergistic effect of PMA on SF-1/Ad4BP-induced transcription, and 3) the importance of the SF-1/Ad4BP regulatory element in the regulation of the 3beta-HSD II promoter.
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PMID:Synergistic activation of the human type II 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase promoter by the transcription factor steroidogenic factor-1/adrenal 4-binding protein and phorbol ester. 906 66


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