Showing papers on "Hydroxysteroid dehydrogenase published in 1994"
TL;DR: The 11β-hydroxysteroid dehydrogenase (11βHSD) as mentioned in this paper was found to protect the nonselective mineralocorticoid receptor from occupation by glucocorticity, and to modulate access of glucoc Corticoid to glucoc corticoid receptors resulting in protection of the fetus and gonads.
678 citations
TL;DR: Four substitution and two splice junction mutations were identified in the 17βHSD3 genes of five unrelated male pseudohermaphrodites that severely compromised the activity of the 17 β–HSD type 3 isozyme.
Abstract: Defects in the conversion of androstenedione to testosterone in the fetal testes by the enzyme 17β–hydroxysteroid dehydrogenase (17β–HSD) give rise to genetic males with female external genitalia. We have used expression cloning to isolate cDNAs encoding a microsomal 17β–HSD type 3 isozyme that shares 23% sequence identity with other 1 7β–HSD enzymes, uses NADPH as a cofactor, and is expressed predominantly in the testes. The 17βHSD3 gene on chromosome 9q22 contains 11 exons. Four substitution and two splice junction mutations were identified in the 17βHSD3 genes of five unrelated male pseudohermaphrodites. The substitution mutations severely compromised the activity of the 17β–HSD type 3 isozyme.
574 citations
TL;DR: In this paper, the authors further refined the structure of the short-chain dehydrogenase with its cofactor, nicotinamide adenine dinucleotide (NAD), and solvent molecules, at the same resolution.
191 citations
TL;DR: It is clear that major efforts should now be turned towards intracrinology in order to understand better the physiological mechanisms controlling local steroid formation in peripheral target tissues and thus to develop novel therapeutic approaches that take into account the high proportion of steroids that are made locally.
Abstract: Summary In addition to the classical steroidogenic tissues, namely the ovaries, testes, adrenals and placenta, a large series of human peripheral tissues possess all the enzymatic systems required for the formation of active androgens and oestrogens from a relatively large supply of precursor steroids provided by the adrenals. This chapter describes the structure, function, tissue-specific expression and regulation of the 3β-HSD and 17β-HSD gene families as well as some information about the aromatase gene. While, so far, most therapeutic approaches have been aimed and limited at controlling steroid formation by the classical steroidogenic tissues, it is clear that major efforts should now be turned towards intracrinology in order to understand better the physiological mechanisms controlling local steroid formation in peripheral target tissues and thus be in a position to develop novel therapeutic approaches that take into account the high proportion of steroids that are made locally and are responsible for the growth and function of normal as well as cancerous tissue.
83 citations
TL;DR: These cytokines may play an important role in regulating E2DH activity in breast cancer cells and may act synergistically in vivo to enhance the formation of E2 in breast tumours.
69 citations
TL;DR: The steroid binds at the catalytic site in a mode much like the previously proposed mode of binding of the substrate cortisone, and accounts for the inhibition of 3 α ,20 β -HSD.
52 citations
TL;DR: A multiple sequence alignment of these proteins, when combined with the recently determined tertiary structure of Streptomyces hydrogenans 3 alpha, 20 beta-hydroxysteroid dehydrogenase and a homologous enzyme, rat dihydropteridine reductase, identifies segments and residues that are likely to be structurally important in the functioning of these enzymes.
45 citations
TL;DR: In this article, the authors reported the isolation and characterization of a full length cDNA encoding rat 20αhydroxysteroid dehydrogenase derived from rat corpus luteum RNA.
35 citations
TL;DR: The present data show that the baculovirus expression system can provide active 17 beta-HSD that is functionally identical to its natural counter-part and easy to purify in quantities suitable for its physico-chemical studies.
29 citations
24 citations
TL;DR: In this article, the distribution of 3α-hydroxysteroid dehydrogenase in different regions of the brain in rats was evaluated by activity assay and by Western immunoblottin using a monoclonal antibody against liver 3αhydroxsteroid dehydrogenase as the probe.
TL;DR: It is suggested that bFGF may have a regulatory role in placental estrogen metabolism via its effects on 17-HSD type 1 through its regulation by basic fibroblast growth factor in choriocarcinoma cell lines.
TL;DR: The N-terminal amino acid sequence analysis of purified enzyme suggests that 17 alpha-HSDH may belong to a disulfide reductase gene family, which is highly specific for NADP+ and the 17alpha-hydroxy group of C-19 steroids.
TL;DR: In this article, the synthesis of eight 16α-propyl derivatives of estradiol is described, and structure-activity relationships are discussed, with IC50 values of 0.42 and 0.46 μM, respectively.
TL;DR: To identify regions of the enzyme involved in steroid hormone recognition, mechanism-based inactivators and site-directed mutagenesis have been employed and it was found that compounds 1 and 3 inactivated 3 alpha-HSD only in the presence of NAD+.
Abstract: Rat liver 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD, EC 1.1.1.50) inactivates circulating androgens, progestins, and glucocorticoids. 3 alpha-HSD is a member of the aldo-keto reductase superfamily, and the X-ray structure of the apoenzyme shows the presence of an (alpha/beta)8 barrel [Hoog, S. S., Pawlowski, J. E., Alzari, P. M., Penning, T. M., & Lewis, M. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 2517-2521]. As yet, a three-dimensional structure of the ternary complex E.NADPH.steroid is unavailable. To identify regions of the enzyme involved in steroid hormone recognition, we have employed mechanism-based inactivators and site-directed mutagenesis. (3 RS)-1,10-Seco-5 alpha-estr-1-yne-3,17 beta-diol (1) and (17 RS)- 17-hydroxy-14,15-secoandrost-4-en-15-yn-3-one (3) are secosteroids which contain latent Michael acceptors (alpha,beta-unsaturated alcohols) at opposite ends of the steroid nucleus (at the C-3 and C-17 positions, respectively). It was found that compounds 1 and 3 inactivated 3 alpha-HSD only in the presence of NAD+. The requirement for cofactor implies that 1 and 3 are oxidized to the corresponding alpha,beta-unsaturated ketones for inactivation to occur. Chemically prepared 17 beta-hydroxy-1,10-seco-5 alpha-estr-1-yn-3-one (2) and 14,15-secoandrost-4-en-15-yne-3,17-dione (4), the presumed products of 1 and 3 oxidation, behaved as stoichiometric inactivators of 3 alpha-HSD. In the presence and absence of NAD+, 2 and 4 inactivated > 50% of the enzyme in 10 s or less.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The objective of the present study was to define the molecular regulation of rat hepatic 3 alpha-HSDH in response to the key effectors of cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in bile acid biosynthesis.
TL;DR: Synthesis of 6 (3-hydroxy-19-nor-17α-pregna-1,3,5(10)-triene-21,17β-carbolactone), the first inhibitor of 17β-HSD, was performed, using human placental microsomes and 4-androstene-3,17-dione as substrate.
TL;DR: The data suggest that 17 beta-hydroxysteroid dehydrogenase may exist in phosphorylated forms and that phosphorylation may regulate the activity of 17 Beta-Hydroxysteroids dehydrogenases in vivo.
TL;DR: It is demonstrated here that the 17 beta-HSD activity in meningioma tissue homogenate is both estrogenic and androgenic with Km values of 2.4, 0.7, and 2.0 microM for E2, E1, testosterone (T), and delta 4-androstenedione (delta 4), respectively, and NAD(+)-NADH is almost exclusively used as cofactor in this tissue.
Abstract: Meningioma benign tumors possess significant levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Two different 17β-HSDs have been cloned and characterized. The cytosolic 17β-HSD I which exclusively catalyzes the interconversion of 17β-estradiol (E2) and estrone (E1) preferentially uses NADP+ and NADPH as cofactors. In contrast, the mitochondrial-microsomal 17β-HSD II catalyzes both the estrogenic as well as the androgenic substrates of the 17β-HSD and uses NAD+ and NADH as cofactors. We demonstrated here that the 17β-HSD activity in meningioma tissue homogenate is both estrogenic and androgenic with Km values of 2.4, 0.4, 14.7, and 2.0 µM for E2, E1, testosterone (T), and Δ4-androstenedione (Δ4), respectively. NAD+-NADH is almost exclusively used as cofactor in this tissue. Moreover, fractionation of meningioma tissue revealed that most of the 17β-HSD activity is present in the mitochondrial-microsomal fraction. Although Northern blot analysis on meningiomas with a specific probe for human 17β-HSD I showed no band, the specific cDNA probe of human 17β-HSD II hybridized at the expected size of 1.5 kb, which was also present in placenta. On four different meningioma tumors, we were able to correlate 17β-HSD II mRNA expression to high levels of 17β-HSD activity. Taken together, the present data suggest that the meningioma 17β-HSD could be the 17β-HSD II.
TL;DR: DA mainly stimulated 3 beta -HSD activity of the PMSG-treated rat ovary which regulated P synthesis, and DA alone did not affect the E2 level in the media and aromatase activity.
Abstract: Little is known about the dopamine system in the ovary. The present study has been undertaken to investigate the effect of dopamine (DA) on the ovarian steroidogenic enzymes of pregnant mare serum gonadotropin (PMSG)-treated immature rats. Ovarian cells from PMSG-treated rats were cultured for 1-5 hours with or without DA, D1 agonists or bulbocapnine (Bul)(D1 antagonist). Progesterone (P) and estradiol (E2) in the media were assayed by specific RIAs. The enzyme activities were assayed by adding radioactive substrates in the media before incubation. DA and D1 agonists increased P in the media which was caused by the increment of 3 beta -hydroxysteroid dehydrogenase (3 beta -HSD) activity because cholesterol side chain cleavage enzyme (CSCC) activity showed no significant change. The stimulating effects of DA and DA agonists on P and 3 beta -HSD activity were inhibited by Bul. DA showed no effect on 17 alpha-hydroxylase activity. DA decreased 17.20 lyase activity, but this decrement was probably a non specific effect. DA alone did not affect the E2 level in the media and aromatase activity. The present results suggest that DA mainly stimulated 3 beta -HSD activity of the PMSG-treated rat ovary which regulated P synthesis.
Journal Article•
TL;DR: In this paper, carboxylic acids of N(3)-pyrazole substituted 1,2,3-benzotriazin-4-(3H)-ones and quinazolin-4-1H-ones were prepared and tested for the inhibitory property of 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol.
Abstract: Some carboxylic acids of N(3)-pyrazole substituted 1,2,3-benzotriazin-4-(3H)-ones and- quinazolin-4-(3H)-ones were prepared and tested for the inhibitory property of 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol. The results indicated that the degree of inhibition can be used to predict the antiinflammatory potency of the compounds described.