Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5 alpha-Dihydrotestosterone 3 alpha(beta)-hydroxysteroid dehydrogenase [3 alpha(beta)-HSDH] [EC 1.1.1.50/EC 1.1.1.51] which catalyses the conversion of 5 alpha-dihydrotestosterone (5 alpha-DHT) to both 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3 beta,17 beta-diol was purified to an apparent homogeneous state using cytosol of three human hyperplastic prostates by a 4-step purification procedure. After each purification step 3 alpha-HSDH activity was coincident with 3 beta-HSDH activity. On average, specific 3 alpha-HSDH activity was enriched 856-fold, specific 3 beta-HSDH activity 749-fold compared to human prostatic cytosol using anion exchange, hydrophobic interaction, gel filtration and affinity chromatography. Examination of the purified enzyme by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS) revealed a single protein band with silver staining. The molecular weight of the enzyme was estimated as 33 kDa by SDS-polyacrylamide gel electrophoresis and as 28 kDa by Sephacryl S-200 gel filtration indicating that the native 3 alpha(beta)-HSDH is a monomer. In the presence of the preferred co-factor, NADPH, the purified enzyme had a mean apparent Km for 5 alpha-DHT of 3.9 microM and a Vmax of 93.3 nmol (mg protein)-1 h-1 with regard to 3 alpha-HSDH activity, and a Km of 6.3 microM and a Vmax of 20.6 nmol (mg protein)-1 h-1 with regard to 3 beta-HSDH activity.
J Steroid Biochem Mol Biol 1992 May
PMID:Purification and properties of the 5 alpha-dihydrotestosterone 3 alpha(beta)-hydroxysteroid dehydrogenase from human prostatic cytosol. 160 44

By using immature porcine Leydig cells cultured in defined medium as a model, transforming growth factor-beta (TGF beta) was shown to exert a dramatic inhibitory effect on their basal and human chorionic gonadotropin (hCG) (or 8-bromo-cyclic AMP) stimulated dehydroepiandrosterone secretion, in the presence or absence of saturating concentrations of exogenous (low density lipoprotein) cholesterol substrate. In contrast, TGF beta exerted both a stimulating and inhibitory effect on testosterone secretion: while hCG-stimulated testosterone secretion was enhanced by low doses of TGF beta (0.06-0.4 ng/ml, 48 h), it was decreased with higher concentrations of TGF beta (2.5-10 ng/ml, 48 h). The data obtained show that the inhibitory action of TGF beta on testicular steroidogenesis was related to a decrease in pregnenolone formation by affecting a step(s) distal to cyclic AMP formation but before cholesterol association with cytochrome P-450 side-chain cleavage. As for the stimulatory effect of TGF beta on testosterone formation, this was mainly related to an increase (about 2-fold) in 3 beta-hydroxysteroid dehydrogenase/isomerase activity (ED50 0.05 ng/ml, 2 X 10(-13) M). The results indicate that the (short-term) steroidogenic stimulatory action of luteinizing hormone (LH)/hCG is antagonized by high concentrations of TGF beta by decreasing pregnenolone formation while it is enhanced by the stimulating action of low concentrations of TGF beta exerted on 3 beta-hydroxy steroid dehydrogenase/isomerase activity.
Mol Cell Endocrinol 1989 Dec
PMID:On the mechanisms involved in the inhibitory and stimulating actions of transforming growth factor-beta on porcine testicular steroidogenesis: an in vitro study. 253 15

Hybrids constructed by fusing mouse Leydig cells with mouse adrenal Y1 cells were able to randomly express all the parental specific traits but for the response to gonadotropin (hCG) and corticotropin (ACTH): three of them, YDYL 14, 17 and 19, metabolized both progesterone and dehydroepiandrosterone into testosterone accounting for 17 alpha-hydroxylase, 17-20-lyase, 17-ketoreductase and 3 beta-hydroxysteroid dehydrogenase activities. Under basal conditions, 17 alpha-hydroxylase and 17-20-lyase activities were high in the three clones as compared to parental Leydig cells, and were no longer stimulated by cAMP in YDYL 17 and 19. The hybrids responded to various hormones such as prostaglandin E2 (PGE2), vasoactive intestinal peptide (VIP) and prolactin (PRL) which are not directly implicated in the expression of steroidogenesis; they generally retained the Y1 morphological response to 8-bromo cAMP. On extended culture, reexpression of ACTH sensitivity occurred in one clone, YDYL 9. This reexpression was correlated with a Robertsonian translocation between mouse chromosomes 2 and 11, while extinction required the presence of an intact mouse chromosome 11.
Mol Cell Endocrinol 1988 Dec
PMID:Steroidogenesis expression depends on negative control(s): analysis in Leydig X adrenal intraspecific cell hybrids. 285 Sep 56

The effect of trilostane and aminoglutethimide on steroidogenesis was studied on isolated guinea pig adrenocortical cells in order to verify whether, in addition to the inhibitory influence of trilostane on 3beta-hydroxysteroid dehydrogenase and isomerase and the inhibition by aminoglutethimide of pregnenolone formation, these inhibitors may also affect other enzymatic steps of cortisol synthesis. While trilostane completely abolished cortisol production in response to ACTH with concomitant enhancement in pregnenolone and 17-hydroxypregnenolone formation, the conversion of progesterone, 17-hydroxyprogesterone and 11-deoxycortisol into cortisol was not affected by the presence of the inhibitor. Contrasting with this specific inhibitory effect of trilostane, aminoglutethimide inhibited not only pregnenolone formation but also several other enzymatic steps involved in the conversion of this precursor of steroidogenesis into cortisol. Among these additional effects of aminoglutethimide on steroidogenesis, the inhibition of 11 beta-hydroxylation was clearly demonstrated.
Mol Cell Endocrinol 1984 Aug
PMID:On the specificity of the inhibitory effect of trilostane and aminoglutethimide on adrenocortical steroidogenesis in guinea pig. 608 27

The enzyme 11 beta-hydroxy steroid dehydrogenase (11 beta-OHSD) was described and its location in various organs noted more than 30 years ago (Mahesh and Ulrich, 1960; Jenkins, 1966). 11 beta-OHSD inactivates circulating glucocorticoids by transforming the hydroxyl group at the 11-carbon to a keto group. This chemical reaction has taken on a greater degree of physiologic and clinical significance in recent years. It has been suggested that 11 beta-OHSD, present in mineralocorticoid target tissues, can act as a 'guardian' over the mineralocorticoid receptor by transforming circulating endogenous glucocorticoids to their respective 'biologically inert' 11-dehydro derivatives (Edwards et al., 1988; Funder et al., 1988). These derivatives do not bind to mineralocorticoid receptors (MR) while both their parent compounds and mineralocorticoids bind to cloned MR with equal affinity (Arriza et al., 1987). 11 beta-OHSD has generated a growing sense of scientific excitement since this enzyme may represent one of a family of metabolic pathways or mechanisms which can regulate steroid induced renal reabsorption of sodium. Such 'protective' enzymatic pathways, present in the kidney and elsewhere, may not only control the access of glucocorticoids to MR, but control the access of glucocorticoids to glucocorticoid receptors (GR) (Teelucksingh et al., 1990; Monder, 1990) as well as access of mineralocorticoids to their own receptors. This review will focus on this concept of a family of protective enzymatic pathways and the possible physiological implications.
Mol Cell Endocrinol 1993 Nov
PMID:Interactions between glucocorticoids and mineralocorticoids in the regulation of renal electrolyte transport. 814 89

After the incubation of minced mammary tissues from non-lactating/non-pregnant (NL/NP), nonlactating/pregnant (NL/P), fully lactating (FL) and late-lactating (LL) cows with [14C]-labelled pregnenolone or progesterone and dehydroepiandrosterone (DHEA), the following metabolites were identified at all stages: 20alpha-dihydropregnenolone, progesterone (from pregnenolone), 5alpha-pregnanedione, 5alpha-pregnan-3beta-ol-20-one, 20alpha- and 20beta-dihydroprogesterone (from progesterone), 5-androstene-3beta,17beta-diol, 5alpha-androstanedione, 5alpha-androstan-3beta-ol-17-one, androstenedione, testosterone and DHEA acyl ester (from DHEA). These products indicate the occurrence of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase, 17beta-hydroxysteroid oxidoreductase (17beta-HOR), 20alpha- and 20beta-hydroxysteroid dehydrogenases, steroid 5alpha-reductase and acyl transferase activities. Incubation of mammary tissue homogenates with [1,2,6,7-(3)H]androstenedione and testosterone confirmed the presence of a 17beta-HOR acting prevalently in a reductive way but failed to show evidence of any aromatase activity beyond background level. When total RNA from mammary tissues of NL/NP and LL cows was reverse-transcribed and amplified by polymerase chain reaction (PCR) with three sets of primers specific for bovine P450scc, P450c17 and P450arom cDNAs, no fragment of the expected size could be detected on gel. Southern analysis with corresponding digoxigenin-labelled ovarian probes, however, gave a positive signal for P450arom cDNA in five out of eight samples of LL mammary tissue. These data indicate that the bovine mammary gland has very limited steroidogenic capabilities that are essentially compatible with the terminal activation of circulating steroids from steroidogenic endocrines. It is uncertain, however, whether this conclusion applies to anestrous or ovariectomized lactating cows as well.
J Steroid Biochem Mol Biol 1996 Nov
PMID:Occurrence of steroidogenic enzymes in the bovine mammary gland at different functional stages. 901 Mar 26

Ecdysteroid biosynthesis was analyzed in vitro using dissociated Y-organ cells from the shore crab Carcinus maenas. 3-Dehydroecdysone (3DE) was detected as a minor secretory product, in addition to the formerly identified end-products 25-deoxyecdysone and ecdysone (E). In conversion studies, 3DE was formed from tritiated 5beta-ketodiol (2,22,25-trideoxyecdysone), 2,22-deoxyecdysone and 2-deoxyecdysone but not from E. Further experiments were performed in order to understand the interconversions between 3-oxo and 3beta-OH compounds in the crab Y-organ. The enzyme involved in 3beta-dehydrogenation was not ecdysone oxidase, a soluble enzyme found in peripheral tissues of many arthropods but it presented strong similarities with 3beta-hydroxysteroid dehydrogenase enzymes from vertebrates: it was membrane-bound and NAD+-dependent. Moreover, a NADH-dependent 3beta-reduction of several 3-oxo-ecdysteroids was obtained using the same microsomal fraction (100,000 x g pellet) of Y-organs, indicating that the reaction might be reversible. As this activity was specific of molting glands, we hypothesize that there is at least one 3beta-hydroxysteroid dehydrogenase enzyme involved in the biosynthetic pathway of ecdysteroids.
Mol Cell Endocrinol 1997 Apr 04
PMID:Involvement of a 3beta-hydroxysteroid dehydrogenase activity in ecdysteroid biosynthesis. 914 85

The plasma levels of deoxycorticosterone sulfate (DOC-SO4) in near-term pregnant women are approximately 100 times those in plasma of men or non-pregnant women. Yet, neither the tissue site of synthesis nor the precursor of DOC-SO4 that enters maternal plasma is known. Several potential sources have been excluded: plasma DOC-SO4 is not derived from plasma DOC; and the secretion of C21-steroids (other than aldosterone) from the maternal adrenals during human pregnancy is not increased. Similarly, the transfer of DOC-SO4 from fetal plasma cannot account for the high level of DOC-SO4 in the maternal compartment, and a reduced clearance of plasma DOC-SO4 during pregnancy cannot account for the high levels of DOC-SO4. Indeed, the rate of clearance of DOC-SO4 from plasma is 10-100 times that of most other steroid sulfates. To address this question further, we evaluated the possibility that fetal plasma pregnenolone-3,21-disulfate serves as a precursor for DOC-SO4 formation in the placenta. The preferential hydrolysis of the 3beta-sulfate of pregnenolone-3,21-disulfate in placenta would give rise to pregnenolone-21-monosulfate, which, if acted upon by placental 3beta-hydroxysteroid dehydrogenase/delta5 --> 4 isomerase, could give DOC-SO4. [3H]Pregnenolone-3,21-disulfate was incubated with minces of human placental tissue for 5, 20, 60 and 120 min. Radiolabelled DOC-SO4, DOC, and pregnenolone-21-monosulfate were isolated from the incubation media and quantified. After a 5 min incubation, 7.5% of substrate was converted to DOC-SO4; and after 20, 60 and 120 min approximately 30% of the [3H]pregnenolone-3,21-disulfate was recovered from the media of these incubations as [3H]DOC-SO4. [3H]DOC was also present in the incubation media and the concentrations of this product increased as a function of incubation time. Therefore, pregnenolone-3,21-disulfate, which is present in very high concentrations in fetal plasma (approximately 1000 ng/ml), is metabolized in the placenta to DOC-SO4. Because of the fetal and maternal vascular arrangements of the hemochorioendothelial placenta of human pregnancy, steroids produced in syncytiotrophoblasts preferentially enter the intervillous space; thus, fetal plasma pregnenolone-3,21-disulfate may serve as a placental precursor of maternal plasma DOC-SO4.
J Steroid Biochem Mol Biol 1997 Mar
PMID:Origin of deoxycorticosterone sulfate (DOC-SO4) in plasma of pregnant women: pregnenolone-3,21-disulfate is a placental precursor of DOC-SO4. 921 25

TGF beta1 has been detected by immunohistochemistry in the rat fetal testis. Therefore, we attempted to determine whether this factor can act as a local regulator of Leydig cell function during fetal development. An inhibitory effect of TGF beta1 on basal and luteinizing hormone (LH)-stimulated testosterone secretion by fetal testes in vitro was observed only with testes from 13.5 day-old fetuses and not with testes from older stages. The lack of effect of exogenous TGF beta1 in organ culture after day 13.5 might be related to an elevated intratesticular concentration that would already exert maximal biological effect. On the contrary, in a model of dispersed testicular cells in culture, TGF beta1 was able to inhibit LH-stimulated testosterone production by fetal Leydig cells from 16.5 and 20.5 day-old fetuses. This inhibition of LH-stimulated testosterone production was dose- and time-dependent and was maximal after 48 h of treatment with 1 ng/ml TGF beta1, with testosterone secretion being reduced to 25% of control values. Inhibition of testosterone secretion was also observed in basal and dbcAMP-stimulated conditions, suggesting that one site of action of TGF beta1 is located after the production of cAMP. However, TGF beta1 was also able to inhibit LH-induced cAMP production. As demonstrated by the transformation of steroidogenic precursors into testosterone, TGF beta1 did not significantly alter 3beta-hydroxysteroid dehydrogenase (3beta HSD) activity but induced a strong inhibition of cytochrome P450 17alpha-hydroxylase/C17-20 lyase (P450C17) activity which was associated with a marked diminution of cytochrome P450C17 mRNA levels (26% of control values) but not of cytochrome P450scc mRNA. In addition to its effect on steroidogenesis, TGF beta1 exhibited morphogenic actions on the fetal testicular cells, inducing spreading when the cells were adherent and aggregation when the cells were cultured in conditions of lesser adherence and without any significant effect on either total cell number or 3beta HSD positive cells. Taken together these results suggest that TGF beta1 likely plays a morphogenic and physiological role very early in the fetal testis via paracrine/autocrine mechanisms.
Mol Cell Endocrinol 1997 Jul 04
PMID:Transforming growth factor beta1 inhibits steroidogenesis in dispersed fetal testicular cells in culture. 925 60

Colony-stimulating factor-1 (CSF-1) is the principal regulator of cells of the mononuclear phagocytic lineage that includes monocytes, tissue macrophages, microglia, and osteoclasts. Macrophages are found throughout the reproductive tract of both males and females and have been proposed to act as regulators of fertility at several levels. Mice homozygous for the osteopetrosis mutation (csfm[op]) lack CSF-1 and, consequently, have depleted macrophage numbers. Further analysis has revealed that male csfm(op)/csfm(op) mice have reduced mating ability, low sperm numbers, and 90% lower serum testosterone levels. The present studies show that this low serum testosterone is due to reduced testicular Leydig cell steroidogenesis associated with severe ultrastructural abnormalities characterized by disrupted intracellular membrane structures. In addition, the Leydig cells from csfm(op)/ csfm(op) males have diminished amounts of the steroidogenic enzyme proteins P450 side chain cleavage, 3beta-hydroxysteroid dehydrogenase, and P450 17alpha-hydroxylase-lyase, with associated reductions in the activity of all these steroidogenic enzymes, as well as in 17beta-hydroxysteroid dehydrogenase. The CSF-1-deficient males also have reduced serum LH and disruption of the normal testosterone negative feedback response of the hypothalamus, as demonstrated by the failure to increase LH secretion in castrated males and their lack of response to exogenous testosterone. However, these males are responsive to GnRH and LH treatment. These studies have identified a novel role for CSF-1 in the development and/or regulation of the male hypothalamic-pituitary-gonadal axis.
Mol Endocrinol 1997 Oct
PMID:Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. 932 46


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