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)

Experiments were carried out to investigate the abundance of mRNA for luteotrophic receptors and steroidogenic elements in the ovaries and corpora lutea of mink during the embryonic diapause, peri-implantation and postimplantation pregnancy. The second aim was to determine whether the mink placenta synthesized progesterone. Homologous cDNA probes for the mink LH and prolactin receptors were generated by the polymerase chain reaction. Heterologous cDNA probes for steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase-delta 4-delta 5 isomerase (3 beta HSD) were also used. The abundance of mRNA encoding the prolactin receptor was low during the period of embryonic diapause and increased concurrent with circulating progesterone. The abundance of LH receptor message reached peak values during the peri-implantation period followed by maintenance of a steady-state after implantation. The abundance of StAR and P450scc messages appeared not to vary during gestation, while that for 3 beta HSD was correlated with changes in circulating progesterone. There was no evidence of 3 beta HSD activity or transcripts in the placenta. These results indicate that prolactin and LH are necessary for activation of the corpus luteum during the period of embryonic diapause, and for its maintenance during postimplantation gestation. The mink placenta does not synthesize progesterone.
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PMID:Luteal and placental characteristics of carnivore gestation: expression of genes for luteotrophic receptors and steroidogenic enzymes. 940 81

Immune-endocrine interactions are important to the regulation of Leydig cell steroidogenesis. We have shown previously that both tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1-beta) inhibit 8-bromo-cAMP-(8-Br-cAMP)-stimulated steroidogenesis in mouse Leydig cells. TNF and IL-1 both inhibit cAMP-stimulated testosterone production as well as mRNA and protein levels of cholesterol side chain cleavage enzyme (P450scc) and 17 alpha-hydroxylase/C17,20 lyase (P450c17) in mouse Leydig cells. Neither TNF nor IL-1 affects basal levels of P450scc mRNA and protein. In the present study, we tested the effects of TNF and IL-1 on basal testosterone production and 8-Br-cAMP-stimulated 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase (3 beta HSD) expression in Leydig cells. Purified and macrophage-depleted Leydig cells were cultured for 5 d with daily changes of media, and then treated with increasing concentrations of recombinant mouse TNF or IL-1 in the presence or absence of 8-Br-cAMP (50 microM) for 24 h. The media were collected for testosterone RIA and RNA and protein were extracted from cells. Basal testosterone production was inhibited by TNF, but not IL-1. Treatment of Leydig cells with 8-Br-cAMP alone caused a marked increase in 3 beta HSD mRNA, and protein levels. Both TNF and IL-1 inhibited cAMP-stimulated 3 beta HSD mRNA and protein levels, but only TNF inhibited basal 3 beta HSD expression. These results demonstrate that TNF and IL-1 have different effects on basal steroidogenesis in Leydig cells and suggest that TNF-mediated inhibition of basal testosterone production may be owing to the inhibition of basal 3 beta-HSD expression in Leydig cells.
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PMID:Differential effects of tumor necrosis factor-alpha and interleukin-1 on 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase expression in mouse Leydig cells. 965 65

Neurosteroids are now known to be synthesized de novo in the nervous system through mechanisms at least partly independent of peripheral steroidogenic glands. In mammals, the presence of the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and the enzyme 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) has been well established in the brain, whereas limited information has been available on the enzyme 17alpha-hydroxylase/c17, 20-lyase (cytochrome P450c17), which converts pregnenolone to dehydroepiandrosterone, one of the most abundant neurosteroids. In addition, little is known regarding developmental changes in these steroidogenic enzymes during postnatal life. Thus, the pathway of neurosteroid formation in the brain is still incomplete. Therefore, we examined expressions of the messenger RNAs (mRNAs) encoding for three key enzymes, P450scc, P450c17 and 3beta-HSD, in the rat brain at different postnatal ages using RT-PCR analysis. The expression of P450scc mRNA was found throughout the brain at the same level, while the 3beta-HSD mRNA expression was higher in the cerebellum and cerebrum than in other brain regions. The P450c17 mRNA was highly expressed in the mesencephalon. On the other hand, higher expressions of the cerebellar and cerebral 3beta-HSD mRNAs were observed only in neonatal life. In contrast, the expression of P450scc mRNA was relatively constant during neonatal life and in adulthood. A similar constant expression of the P450c17 mRNA was evident in the mesencephalon. Serial Southern hybridization in this study confirmed the specific mRNA expression corresponding to each enzyme. These results suggest that in the postnatal rat the expression of 3beta-HSD or P450c17 mRNA may be age- or region-dependent, unlike the P450scc mRNA expression.
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PMID:Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes p450scc, P450c17 and 3beta-HSD in the postnatal rat brain. 972 6

Recently, we have demonstrated, using biochemical and immunochemical methods, that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and produces pregnenolone and its sulfate ester. To clarify progesterone biosynthesis in the avian brain, therefore, we examined the expression of messenger RNA (mRNA) encoding for the enzyme 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) and its enzymatic activity using the quail. RT-PCR analysis together with Southern hybridization indicated the expression of 3beta-HSD mRNA in the brain of sexually mature birds but with no clear-cut sex difference. Employing biochemical techniques combined with HPLC analysis, the conversion of pregnenolone to progesterone was found in brain slices of mature males. Progesterone biosynthesis was increased in a time dependent manner and completely abolished by trilostane, a specific inhibitor of 3beta-HSD. The enzymatic activity of 3beta-HSD was greatest in the cerebrum and lowest in the mesencephalon. A specific RIA indicated that progesterone concentrations in the different brain regions closely followed the level of 3beta-HSD activity. High levels of progesterone concentration were observed in the diencephalon and cerebrum with lowest values in the mesencephalon. Progesterone levels in the brain regions were significantly higher than those in the plasma. These results suggest that the avian brain possesses not only cytochrome P450scc but also 3beta-HSD and produces progesterone. It is also indicated that progesterone biosynthesis in the avian brain may be region-dependent.
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PMID:Expression and activity of 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase in different regions of the avian brain. 1008 43

Ovarian interstitial cells (OICs) are a common feature of mammalian gonads but little is understood concerning their origin or functional significance. This study investigated the development and steroidogenic potential of OIC in feral and colony-reared feline queens. Reproductive tracts, collected from a total of 50 female colony and feral cats, were fixed and analyzed by morphometry. Ovarian sections were also immuno-stained for the expression of the steroidogenic enzymes 17alpha-hydroxylase/17,20 lyase cytochrome P450 (P450c17), 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD), and aromatase. These findings were related to serum estradiol and testosterone concentrations and to the degree of existing cystic endometrial hyperplasia (CEH). Feral cats had three times as many OICs as colony-reared queens (2713 +/- 855 vs 744 +/- 494 cells/mm(2), P < 0.01). These cells were lipid laden and expressed both P450c17 and 3beta-HSD at levels that were higher than those seen in the theca interna of adjacent follicles. Aromatase expression was undetectable. The pattern of enzyme expression was consistent with development of interstitial tissue from atretic follicles and the potential for continued steroid secretion during the anestrum. The incidence of CEH was higher in older (>5 years old; 88.2%) than in younger (2-4 years; 30%) colony queens (P < 0. 01), whereas no such disease was evident in any of the feral cats. Estradiol levels were higher in colony-reared than in feral cats, but testosterone levels were not different. These data are consistent with the transformation of the theca interna of atretic follicles in cats into OICs that retain a similar, or even enhanced, steroidogenic phenotype. Colony-reared cats exhibit a predisposition to CEH compared with feral queens that is associated with elevated serum estradiol concentrations. Whether or not OICs somehow prevent the development of uterine disease or otherwise reflect a gonadal response to reduced negative feedback on the hypothalamic-pituitary axis remains to be determined.
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PMID:Studies on the origin of ovarian interstitial tissue and the incidence of endometrial hyperplasia in domestic and feral cats. 1052 57

The serum concentration of active glucocorticosteroids depends not only on adrenal synthesis but also on enzymatic activation of 11-dehydro-glucocorticoids in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In order to define the respective involvement of other regulative enzymes in the metabolism of 11-dehydro-glucocorticoids in the liver, the objective of this study was to evaluate the kinetic behavior of NADPH:delta 4-3-ketosteroid-5alpha-reductase (5alpha-reductase, EC 1.3.99.5). The interrelations to liver 11beta-HSD1 will be discussed. The kinetic properties of 5alpha-reductase of the rabbit liver were measured by a radioenzymatic assay and characterized with respect to protein-, substrate-, cosubstrate-, and pH-dependence. Michaelis-Menten enzyme kinetic parameters (Km and Vmax) were obtained for the formation of 5alpha-reduced 11-dehydrocorticosterone and corticosterone metabolites. We found that both 11-dehydrocorticosterone (Km 4.2 x 10(-6) mol/l, Vmax 2,600 pmol x min(-1) x mg(-1)) and corticosterone (Km 0.5 x 10(-6) mol/l, Vmax 38 pmol x min(-1) x mg(-1)) exhibit a high affinity to 5alpha-reductase. With respect to cosubstrate-, pH-dependence and finasteride inhibition, it is likely that 11-dehydrocorticosterone metabolism is primarily controlled by isoenzyme 5alpha-reductase type 1. This study shows that the deactivation of GCS especially of 11-dehydro-glucocorticoids via 5alpha-reductase is an important metabolic pathway in the liver. The metabolic activation of GCS by 11beta-HSD could possibly lead to an excess of GCS in the hepatocytes. Due to 5alpha-reductase activity this excess can be limited - on the level of CORT as well as of 11-DHC.
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PMID:Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase. 1072 9

We have recently demonstrated that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) and produces pregnenolone, pregnenolone sulfate and progesterone from cholesterol. To elucidate the developmental changes in progesterone biosynthesis and its metabolism in the quail brain, we examined the expression and activity of 3beta-HSD and progesterone metabolite(s) during embryonic and post-hatched ages. Both the progesterone concentration and 3beta-HSD mRNA expression in the brain were almost constant during embryonic and post-hatched ages. The conversion of pregnenolone to progesterone (net 3beta-HSD enzymatic activity) was also constant during development and at maturity. However, without radioinert progesterone, the production of progesterone was drastically reduced in the embryonic brain, indicating active progesterone metabolism at the embryonic stage. Biochemical analysis together with HPLC and TLC revealed that only the embryonic brain actively produced 5beta-dihydroprogesterone from progesterone. Thus, progesterone production may be constant during embryonic and post-hatched development and in adulthood, whereas 5beta-dihydroprogesterone may be produced actively only in embryonic life due to 5beta-reductase.
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PMID:Developmental changes in progesterone biosynthesis and metabolism in the quail brain. 1129 66

The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters.
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PMID:Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. 1138 80

Glucocorticoids indirectly alter adrenocortical steroid output through the inhibition of ACTH secretion by the anterior pituitary. However, previous studies suggest that glucocorticoids can directly affect adrenocortical steroid production. Therefore, we have investigated the ability of glucocorticoids to affect transcription of adrenocortical steroid biosynthetic enzymes. One potential target of glucocorticoid action in the adrenal is an enzyme critical for adrenocortical steroid production: 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD). Treatment of the adrenocortical cell line (H295R) with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3beta-HSD mRNA levels alone or in conjunction with phorbol ester. This increase in 3beta-HSD mRNA was paralleled by increases in Steroidogenic Acute Regulatory Protein (StAR) mRNA levels. The human type II 3beta-HSD promoter lacks a consensus palindromic glucocorticoid response element (GRE) but does contain a Stat5 response element (Stat5RE) suggesting that glucocorticoids could affect type II 3beta-HSD transcription via interaction with Stat5. Transfection experiments show enhancement of human type II 3beta-HSD promoter activity by coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with 100nM dexamethasone. Furthermore, removal of the Stat5RE either by truncation of the 5' flanking sequence in the promoter or introduction of point mutations to the Stat5RE abolished the ability of DEX to enhance 3beta-HSD promoter activity. These studies demonstrate the ability of glucocorticoids to directly enhance the expression of an adrenal steroidogenic enzyme gene albeit independent of a consensus palindromic glucocorticoid response element.
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PMID:Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene. 1242 39

The enzyme complex 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) is involved in the biosynthesis of all classes of active steroids. The expression of 3b-HSD in human uterine endometrium during the menstrual cycle and decidua was examined in an effort to understand its role during ova implantation. 3beta-HSD was weakly expressed in the glandular epithelium of the proliferative phase and moderately expressed in the glandular epithelium of secretory phase of the endometrium. In the decidua of the ectopic pregnancy, 3beta-HSD was strongly expressed. The human uterine endometrial 3beta-HSD was identified as being the same type as the placental 3beta-HSD by RT-PCR and sequence analysis. In addition to the expression of 3beta-HSD, P450scc was expressed in the decidua of the ectopic pregnancy. These results suggest that pregnenolone might be synthesized from cholesterol by P450scc de novo and then, it is converted to progesterone by 3beta-HSD in the uterine endometrium. The data implies that the endometrial 3beta-HSD can use not only the out-coming pregnenolone from the adrenal gland but also the self- made pregnenolone to produce progesterone. The de novo synthesis of progesterone in the endometrium might be a crucial factor for implantation and maintenance of pregnancy.
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PMID:Expression of 3beta-hydroxysteroid dehydrogenase and P450 side chain cleavage enzyme in the human uterine endometrium. 1285 14


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