Showing papers on "Hydroxysteroid dehydrogenase published in 2011"
TL;DR: It is found that there are subpockets involved in ligand binding that are considerably different in AKR1C3 relative to the closely related AKR2C1 or AKR3C2 isoforms, which can be used to further improve the binding affinity and selectivity of the currently available AKR 1C3 inhibitors.
111 citations
TL;DR: It is postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1.
Abstract: 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17β-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17β-HSD1 in a recombinant enzyme assay, with high selectivity against 17β-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1. The best inhibitor in the series proved to be 6a, with an IC50 of 270 nM, and with exceptional selectivity for 17β-HSD1 over 17β-HS...
58 citations
TL;DR: Inhibition of 17β-HSD1 inhibitors from the hydroxyphenylnaphthol class by introduction of different heteroaromatic rings as well as substituted phenyl groups showed a good membrane permeation and metabolic stability and was orally available in the rat.
Abstract: Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-depende...
51 citations
TL;DR: Compound 19 turned out to be the most potent and selective inhibitor of 17 β-HSD2 in cell-free assays and had a very good cellular activity in MDA-MB-231 cells, expressing naturally 17β- HSD2.
Abstract: Estrogen deficiency in postmenopausal women or elderly men is often associated with the skeletal disease osteoporosis. The supplementation of estradiol (E2) in osteoporotic patients is known to prevent bone fracture but cannot be administered because of adverse effect. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) oxidizes E2 to its inactive form estrone (E1) and has been found in osteoblastic cells, it is an attractive target for the treatment of osteoporosis. Twenty-one novel, naphthalene-derived compounds have been synthesized and evaluated for their 17β-HSD2 inhibition and their selectivity toward 17β-HSD1 and the estrogen receptors (ERs) α and β. Compound 19 turned out to be the most potent and selective inhibitor of 17β-HSD2 in cell-free assays and had a very good cellular activity in MDA-MB-231 cells, expressing naturally 17β-HSD2. It also showed marked inhibition of the E1-formation by the rat and mouse orthologous enzymes and strong inhibition of monkey 17β-HSD2. It is thus an appropriate...
43 citations
TL;DR: An overview of the different types of AKR1C1 inhibitors and an update on the design of potent and selective inhibitors based on the crystal structure of the enzyme-inhibitor complex are provided.
33 citations
TL;DR: Structural-function studies of aromatase, estrone sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are important to evaluate the molecular basis of the interaction between these enzymes and their inhibitors.
32 citations
TL;DR: A series of compounds producing a strong inhibition of 17β-HSD3 overexpressed in HEK-293 cells (homogenized cells) are identified and a new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile.
29 citations
TL;DR: HPTE, which is the biologically active metabolite of MXC, has the capacity for direct inhibition of 3β-HSD and 17β- HSD3 enzyme activity, presumably associated with suppression of steroidogenesis in gonadal tissues and has implications for testis function.
Abstract: Summary
Human and rat testis microsomes were used to investigate direct inhibitory activities of methoxychlor (MXC) and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). The 3β-HSD and 17β-HSD3 enzymes are involved in the reactions that culminate in androgen biosynthesis in Leydig cells. The results demonstrated that MXC and HPTE inhibited human 3β-HSD activity at a concentration of 10 nm. The half maximal inhibitory concentration (IC50) for MXC inhibition of 3β-HSD was 53.21 ± 15.52 μm (human) and 46.15 ± 17.94 μm (rat), and for HPTE, it was 8.29 ± 2.49 μm (human) and 13.82 ± 2.26 μm (rat). At the higher concentration of 100 μm, MXC did not affect human and rat 17β-HSD3 activity. However, the IC50 for HPTE inhibition of 17β-HSD3 was 12.1 ± 1.9 μm (human) and 32 .0 ± 8.6 μm (rat). The mode of action of MXC and HPTE on 3β-HSD activity was non-competitive with the substrate pregnenolone, but was competitive with the cofactor NAD+. The mode of HPTE inhibition of 17β-HSD3 was non-competitive with the substrate androstenedione, but was competitive with the cofactor NADPH. In summary, our results showed that HPTE, which is the biologically active metabolite of MXC, has the capacity for direct inhibition of 3β-HSD and 17β-HSD3 enzyme activity. Inhibition of enzyme activity is presumably associated with suppression of steroidogenesis in gonadal tissues and has implications for testis function.
23 citations
TL;DR: It was found that Halowax 1051, in all doses used, increased basal T secretion concomitant with a decrease in basal E2 secretion, suggesting non-linear dose-response effect of Halowx 1051 on steroidogenesis and steroidogenic enzymes activity and protein expression.
22 citations
TL;DR: Immunohistochemical analysis revealed that bovine 20α-HSD protein was intensively localized in the large luteal cells during the late estrous cycle and enzymatic activity was similar to that of 20β-hydroxysteroid dehydrogenase.
Abstract: The enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD) catalyzes the conversion of progesterone to its inactive form, 20α-hydroxyprogesterone. This enzyme plays a critical role in the regulation of luteal function in female mammals. In this study, we conducted the characterization and functional analyses of bovine 20α-HSD from placental and ovarian tissues. The nucleotide sequence of bovine 20α-HSD showed significant homology to that of goats (96%), humans (84%), rabbits (83%), and mice (81%). The mRNA levels increased gradually throughout the estrous cycle, the highest being in the corpus luteum (CL) 1 stage. Northern blot analysis revealed a 1.2 kb mRNA in the bovine placental and ovarian tissues. An antibody specific to bovine 20α-HSD was generated in a rabbit immunized with the purified, recombinant protein. Recombinant 20α-HSD protein produced in mammalian cells had a molecular weight of ∼37 kDa. Bacterially expressed bovine 20α-HSD protein showed enzymatic activity. The expression pattern of the 20α-HSD protein in the pre-parturition placenta and the CL1 stage of the estrous cycle was similar to the level of 20α-HSD mRNA expression. Immunohistochemical analysis also revealed that bovine 20α-HSD protein was intensively localized in the large luteal cells during the late estrous cycle.
22 citations
TL;DR: A series of new nonsteroidal and achiral 17β-HSD2 inhibitors, namely N-benzyl-diphenyl-3(or 4)-carboxamide and N-bensyl-5-phenyl-thiophene-2- carboxamide was designed and the compounds were synthesized in a two to three steps reaction.
TL;DR: Further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function, and a molecular docking study provided insight into the protein–ligand interactions of this compound with 17β‐HSD1.
Abstract: An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17β-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nM (cell-free assay) and 78 nM (cellular assay), high selectivity for 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.
TL;DR: A thermostable 7α-hydroxysteroid dehydrogenase from B. fragilis might play multiple functional roles in biosynthesis and metabolism of bile acids, and in the detoxification of xenobiotics containing carbonyl groups in the large intestine, and its broad substrate spectrum offers great potential for finding applications.
TL;DR: Investigation of prenatal exposure to octylphenol at the dose of 50mg/kg body weight on days 1, 7 and 14 of pregnancy on reproductive health of male rats at adulthood revealed poor male reproductive performance, and there was an increase in the mating index in experimental rats with an increased in the pre- and post-implantation losses in rats cohabited with treated animals.
TL;DR: Using quantitative real-time polymerase chain reaction and western blotting analysis, the authors found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in colorectal cancer (CRC) cells.
Abstract: Epidemiological studies have revealed that butyrate and 17β-estradiol (E2) may decrease the incidence of colorectal cancer (CRC). In peripheral tissue, E2 can be produced locally by 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) estrone (E1) reduction. Using quantitative real-time polymerase chain reaction and western blotting analysis, we found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in HT29 and SW707 CRC cells. Chromatin immunoprecipitation analysis showed that upregulation of these transcript levels correlated with an increase in binding of Polymerase II to proximal and distal promoters of HSD17B1. Moreover, we observed that upregulation of HSD17B1 protein levels was associated with increased conversion of E1 to E2 in HT29 and SW707 CRC cells. Since sodium butyrate increases the conversion of E1 to E2, our findings may support the validity of butyrate in the prophylaxis of CRC incidence.
TL;DR: The crystal structure of AKR1C1 complexed with the first structure-based designed inhibitor 3-chloro-5-phenylsalicylic acid bound in the active site is reported and the effects of the mutations on the K(i) value are determined.
TL;DR: It is suggested that variation in H SD17b2 and HSD17b4 does not substantially influence the risk of endometrial cancer in Caucasians, and single nucleotide polymorphisms (SNPs) in these genes may alter the enzyme activity, estradiol levels and risk of disease.
TL;DR: Results show that HSD17B11 transcription in PC cells is regulated by Sp1 and C/EBPα and this process was not mediated by the CCAAT boxes located within its proximal promoter region.
TL;DR: The presence of 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) transcript and protein in receptor positive ER+ and negative ER− Ishikawa endometrial adenocarcinoma (ISH) cells and chromatin immunoprecipitation analysis revealed that apicidin significantly decreased occupation of the first exon of the HSD 17B1 gene by Polymerase II.
Abstract: It has recently been reported that endometrial cancer cells are able to convert estron (E1) to 17β estradiol (E2). We observed the presence of 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) transcript and protein in receptor positive ER+ and negative ER− Ishikawa endometrial adenocarcinoma (ISH) cells. ER+ ISH, but not ER−02 ISH, cells were significantly susceptible to apicidin induced death, and we further used ER−ISH cells to study the effect of apicidin on cellular levels of HSD17B1 transcript and protein. We showed that apicidin significantly lowered HSD17B1 transcript and protein levels in ISH cells. There was no significant effect on HSD17B1 transcript stability. However, chromatin immunoprecipitation analysis revealed that apicidin significantly decreased occupation of the first exon of the HSD17B1 gene by Polymerase II. Since intratumoral E1 to E2 conversion is a significant contributor to the progression of estrogen dependent cancers, and HDAC inhibitors are being tested in anticancer clinical trials, our observations may have clinical value.
TL;DR: A pathway connecting overproduction of TGFβ with increased PSA in prostate cancer is suggested, given that TGFα Rs are recycled with or without ligand, TGF-β1-induced disassociation of the HSDs from TGF β Rs may increase stability and activity of theHSDs.
Abstract: Transforming growth factor β1 (TGF-β1) increases dehydro-epiandrosterone (DHEA) metabolism to androgens and prostate-specific antigen (PSA) in a prostate tissue model where stromal (6S) cells and epithelial (LAPC-4) cells are cocultured. Red clover (RC) isoflavones inhibits transforming growth factor (TGF)-β-induced androgenicity. Mechanisms controlling those activities were explored. Three hydroxysteroid dehydrogenases (HSDs), 3β-HSD, HSD-17β1 and HSD-17β5 involved in metabolizing DHEA to testosterone (TESTO) were investigated. Individual depletion of HSDs in 6S cells significantly reduced TGF-β1/DHEA-induced PSA in LAPC-4 cells in cocultures. Monomer amounts of 3β-HSD were similar without or with TGF-β1 in both cell types but aggregates of 3β-HSD in 6S cells were much higher than those in LAPC-4 cells and were upregulated by TGFβ in 6S cells. Basal and TGF-β1-treated levels of HSD-17β1 and HSD-17β5 in LAPC-4 cells were significantly lower than in 6S cells, whereas levels of HSD-17β1 but not HSD-17β5 were TGFβ inducible. 6S cell HSD genes expression induced by TGFβ or androgen signaling was insignificant to contribute TGF-β1/DHEA-upregulated protein levels of HSDs. RC decreased TGF-β1- upregulation of aggregates of 3β-HSD but not HSD-17β1. Depletion of TGFβ receptors (TGFβ Rs) reduced TGF-β1/DHEA-upregulated HSDs and TESTO. Immunoprecipitation studies demonstrated that TGF-β1 disrupted associations of TGFβ Rs/HSDs aggregates, whereas RC suppressed the dissociations of aggregates of 3β-HSD but not HSD-17β1 from the receptors. Given that TGFβ Rs are recycled with or without ligand, TGF-β1-induced disassociation of the HSDs from TGFβ Rs may increase stability and activity of the HSDs. These data suggest a pathway connecting overproduction of TGFβ with increased PSA in prostate cancer.
TL;DR: In a severely affected child with HSD10 deficiency, undetectable levels of amyloid-β peptide are found in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, α-synuclein, and serotonin metabolites, which highlight the role of Aβ in both early and late periods of life.
Abstract: hydroxysteroid dehydrogenase 10 (HSD10) deficiency is a rare X-linked inborn error of isoleucine catabolism. Although this protein has been genetically implicated in Alzheimer's disease pathogenesis, studies of amyloid- peptide (A) in patients with HSD10 deficiency have not been previously reported. We found, in a severely affected child with HSD10 deficiency, undetectable levels of A in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, -synuclein, and serotonin metabolites. Confirmation of these findings in other patients would help elucidating mechanisms of synaptic dysfunction in this disease, and highlight the role of A in both early and late periods of life.
TL;DR: Interestingly, this steroid derivative showed inhibitory potency towards 17β-HSD1 and did not present residual unwanted estrogenic activity.
TL;DR: A review on AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II), with data on DNA, on the protein encoded, and where the gene is implicated.
Abstract: Review on AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)), with data on DNA, on the protein encoded, and where the gene is implicated.
01 Jun 2011
Patent•
16 Dec 2011
TL;DR: In this article, the 7s-hydroxysteroid dehydrogenase mutants, the sequences which encode these enzyme mutants, and the processes for the preparation of the enzyme mutants and their use in enzymatic reactions of cholic acid compounds were described.
Abstract: The invention relates to novel 7s-hydroxysteroid dehydrogenase mutants, to the sequences which encode these enzyme mutants, to processes for the preparation of the enzyme mutants and to their use in enzymatic reactions of cholic acid compounds, in particular in the preparation of ursodeoxycholic acid (UDCS). The invention also relates to novel processes for the synthesis of UDCS using the enzyme mutants; and to the preparation of UDCS using recombinant, multiply-modified microorganisms.
TL;DR: All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T47-D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide and butylamide derivatives.
Abstract: Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [14C]-E1 (100 nM) into [14C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 μM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T-47D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [14C]-E1 (60 nM) into [14C]-E2 transformation at 1 and 10 μM, respectively.
Patent•
27 May 2011
TL;DR: In this paper, 12 α-hydroxysteroid dehydrogenases, nucleic acid sequences coding for the same, expression cassettes and vectors, recombinant microorganisms containing the corresponding coding nucleic acids sequences, a method for producing said 12α-hydroxsteroid de-hydrogenase, a mechanism for enzymatic oxidation of 12 α -hydroxyl-steroid using said enzyme, and a method of 12-ketosteroid reduction of 12 -ketosteroids using said enzymes.
Abstract: The invention relates to 12 α-hydroxysteroid dehydrogenases, nucleic acid sequences coding for the same, expression cassettes and vectors, recombinant microorganisms containing the corresponding coding nucleic acid sequences, a method for producing said 12 α-hydroxysteroid dehydrogenases, a method for enzymatic oxidation of 12 α-hydroxysteroids using said enzyme, a method for enzymatic reduction of 12-ketosteroids using said enzyme, a method for qualitative or quantitative determination of 12-ketosteroids and/or 12α-hydroxysteroids using said 12α-hydroxysteroid dehydrogenases and a method for production of ursodesoxycholic acid, comprising the enzyme-catalyzed cholic acid oxidation using said 12 α-hydroxysteroid dehydrogenases.