Showing papers on "Hydroxysteroid dehydrogenase published in 2012"
TL;DR: The results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.
Abstract: Background
There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment.
173 citations
TL;DR: It is suggested that cortisol promotes 11-KT production during high temperature-induced masculinization by modulation of hsd11b2 expression and thus drives the morphogenesis of the testes.
Abstract: In many ectotherm species the gonadal fate is modulated by temperature early in life [temperature-dependent sex determination (TSD)] but the transducer mechanism between temperature and gonadal differentiation is still elusive. We have recently shown that cortisol, the glucocorticoid stress-related hormone in vertebrates, is involved in the TSD process of pejerrey, Odontesthes bonariensis. Particularly, all larvae exposed to a male-producing temperature (MPT, 29 C) after hatching showed increased whole-body cortisol and 11-ketotestosterone (11-KT; the main bioactive androgen in fish) levels and developed as males. Moreover, cortisol administration at an intermediate, mixed sex-producing temperature (MixPT, 24 C) caused increases in 11-KT and in the frequency of males, suggesting a relation between this glucocorticoid and androgens during the masculinization process. In order to clarify the link between stress and masculinization, the expression of hydroxysteroid dehydrogenase (hsd)11b2, glucocorticoid receptors gr1 and gr2, and androgen receptors ar1 and ar2 was analyzed by quantitative real time PCR and in situ hybridization in larvae reared at MPT, MixPT, and female-producing temperature (FPT, 17 C) during the sex determination period. We also analyzed the effects of cortisol treatment in larvae reared at MixPT and in adult testicular explants incubated in vitro. MPT and cortisol treatment produced significant increases in hsd11b2 mRNA expression. Also, gonadal explants incubated in the presence of cortisol showed increases of 11-KT levels in the medium. Taken together these results suggest that cortisol promotes 11-KT production during high temperature-induced masculinization by modulation of hsd11b2 expression and thus drives the morphogenesis of the testes.
114 citations
TL;DR: Structural-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR 1C3 inhibition.
Abstract: Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.
93 citations
TL;DR: Type 1 17β-HSD increases 17 β-estradiol exposure in grade 1 EC, thus supporting tumor growth, and this enzyme represents a potential therapeutic target.
Abstract: Context: The local interconversions between estrone (low activity) and 17β-estradiol (potent compound) by 17β-hydroxysteroid dehydrogenases (17β-HSDs) can lead to high 17β-estradiol generation in endometrial cancer (EC). Objective: Examine the balance between the 17β-HSDs reducing estrone to 17β-estradiol (types 1, 5, 12, and 7) and those oxidizing 17β-estradiol to estrone (2, 4, and 8), in EC. Patients and Methods: Reducing and oxidizing 17β-HSD activities (HPLC) and mRNA level (RT-PCR) were assessed in normal post-menopausal (n = 16), peritumoral endometrium (normal tissue beside cancer, n = 13), and 58 EC (29 grade 1, 18 grade 2, 11 grade 3). Results: Grade 1 EC displayed a shifted estrone reduction/17β-estradiol oxidation balance in favor of 17β-estradiol compared with controls. This was more pronounced among estrogen receptor-α (ER-α)-positive biopsies. Type 1 17β-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-α-positive grade 1 EC than c...
61 citations
TL;DR: This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity
Abstract: The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
43 citations
26 Feb 2012
TL;DR: It is proposed that novel type 2 20beta-HSD type 2 in teleost fish are important enzymes in cortisol catabolism.
Abstract: Hydroxysteroid dehydrogenases (HSDs) are involved in metabolism and pre-receptor regulation of steroid hormones. While 17beta-HSDs and 11beta-HSDs are extensively studied in mammals, only few orthologs are characterized in fish. We discovered a novel zebrafish HSD candidate closely related to 17beta-HSD types 3 and 12, which has orthologs in other species. The enzyme catalyzes the conversion of cortisone to 20beta-hydroxycortisone identified by LC-MS/MS. We named the new enzyme 20beta-HSD type 2. All 20beta-HSD type 2 orthologs localize in the endoplasmic reticulum. Zebrafish 20beta-HSD type 2 is expressed during embryonic development showing the same expression pattern as 11beta-HSD type 2 known to oxidize cortisol to cortisone. In adult tissues 20beta-HSD type 2 shows a ubiquitous expression pattern with some minor sex-specific differences. In contrast to other enzymes metabolizing C21-steroids and being mostly involved in reproduction we propose that novel type 2 20beta-HSDs in teleost fish are important enzymes in cortisol catabolism.
40 citations
TL;DR: The results showed that there are clear structure-activity responses for phthalates in the inhibition of both 3β-HSD and 17β- HSD3 activities, and the length of carbon chains in the ethanol moieties of phthalate may determine the potency to inhibit these two enzymes.
37 citations
TL;DR: Four patients with the 46,XY karyotype and 17-β-HSD3 deficiency are reported, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstensione ratio < 0.8.
Abstract: The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively.
32 citations
TL;DR: Human 17b-hydroxysteroid dehydrogenase type 10 is a homotetrameric mitochondrial protein expressed in the liver and several other tissues, including brain and gonad, which plays a role in the metabolism of steroid hormones.
Abstract: Human 17b-hydroxysteroid dehydrogenase type 10 (17bHSD10) is known for its multiple functions and could be involved in the development and progression of many diseases. 17b-HSD10 is a homotetrameric mitochondrial protein expressed in the liver and several other tissues, including brain and gonad. It plays a role in the metabolism of steroid hormones through its 17b-HSD and 3a-HSD activities (Scheme 1),
26 citations
TL;DR: Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC(50) value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17β-HSD1 and an interesting candidate for further biological evaluation.
25 citations
TL;DR: Investigation of sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells and immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds.
Abstract: 17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.
TL;DR: It is shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer.
Abstract: Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implic ...
TL;DR: 5-(3-Bromo-4-hydroxybenzylidene)-3-(4-methoxyphenyl)-2-thioxo-1,3-thiazolidin- 4-one exhibited a promising activity profile and demonstrated significant selectivity over the related 17β-HSD isoenzymes and nuclear receptors.
TL;DR: A new class of 17βHSD2 inhibitors with a 1H‐1,2,4‐triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17β HSD2 inhibitory activity and a good selectivity toward 17 βHSD1, and could be a useful tool to map the unexplored enzyme active site.
Abstract: A series of disubstituted-1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) - a novel and attractive target for the treatment of osteoporosis 17βHSD2 catalyzes the oxidation of the highly active estrogen 17β-estradiol (E2) and androgen testosterone (T) into the weak estrone and androstenedione, respectively Inhibition of this enzyme will locally in the bone lead to an increase in E2 and T levels, two key players in the maintenance of the balance between bone resorption and bone formation In this study, a new class of 17βHSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17βHSD2 inhibitory activity and a good selectivity toward 17βHSD1 They could be a useful tool to map the unexplored enzyme active site
TL;DR: Large-scale Enzymatic Synthesis of 12-Ketoursodeoxycholic acid from Dehydrocholic Acid by Simultaneous Combination of 3α-Hydroxysteroid Dehydrogenase from Pseudomonas testosteroni and 7β-hydroxysteroids Dehydrogensase from Collinsella aerofaciens.
Abstract: 12-Keto-UDCA is an important optically active component for the drug ursodeoxycholic acid (UDCA). Starting from the three-keto compound dehydrocholic acid, the carbonyl groups at position 3 and 7 have to be reduced stereo- and regioselectively. In this case we applied two hydroxysteroid dehydrogenases for this purpose, the NAD-dependent 3α-HSDH from Pseudomonas testosteroni and the NADP-dependent 7β-hydroxysteroid dehydrogenase from Collinsella aerofaciens. Both enzymes can be produced in high yields by an Escherichia coli strain as recombinant proteins. In order to avoid impurities by the 7a-hydroxysteroid dehydrogenase of Escherichia coli, a mutant strain with an inactivated 7a-enzyme was applied for producing the three enzymes. For bioconversion, the dehydrogenases can be used as crude enzyme samples and are applied simultaneously. A 1.8 L batch of 100mM DHCA incubated at pH = 8.0 and 25°C resulted in 80 g crude product with a quite high purity of ≥ 99:5% as judged by HPLC analysis. Graphical Abstract Large-scale Enzymatic Synthesis of 12-Ketoursodeoxycholic Acid from Dehydrocholic Acid by Simultaneous Combination of 3α-Hydroxysteroid Dehydrogenase from Pseudomonas testosteroni and 7β-Hydroxysteroid Dehydrogenase from Collinsella aerofaciens
TL;DR: New insights are given to the transcriptional regulation of 3 βHSD1 and 17βHSD7 and further hints to their involvement in steroid metabolism are given.
Patent•
28 Mar 2012
TL;DR: In this article, a new process for the regioselective enzymatic oxidation of bile acids, salts or derivatives thereof, such as cholic acid, chenodeoxycholic acid or cholic acids methyl ester, by NAD (P) + -dependent HSHDH in the presence of an alcohol dehydrogenase (ADH) and of methyl acetoacetate as a co- substrate for the regeneration of the cofactor NAD(P)+.
Abstract: New process for the regioselective enzymatic oxidation of bile acids, salts or derivatives thereof, such as cholic acid, chenodeoxycholic acid or cholic acid methyl ester, by NAD (P) + -dependent hydroxysteroid dehydrogenase (HSDH) in the presence of an alcohol dehydrogenase (ADH) and of methyl acetoacetate as a co- substrate for the regeneration of the cofactor NAD(P) + .
01 Jan 2012
TL;DR: The results indicate that exposure to arsenic during early stages of development suppresses the male reproduction in adults and hence any toxic insult during embryonic development and lactation suppresses male reproductive potential in adulthood.
Abstract: 4 Abstract: The present study aimed to assess the possible interference of sodium arsenite in F1 generation male mice with special reference to steroidogenic marker enzymes. Mice were divided in to two groups. The mice in first were served as control and received normal tap water. Sodium arsenite administered orally to mice in the second group during pregnancy and lactation at a dose level of 0.4 ppm and analyzed for spermatogenesis and steroidogenesis in next generation adult male mice. The activity levels of selected steroidogenic marker enzymes (3 -hydroxysteroid dehydrogenase and 17 -hydroxysteroid dehydrogenase) decreased significantly in mice exposed to sodium arsenite. The circulatory levels of testosterone decreased in experimental mice with significantly increase in follicle stimulating hormone. The decreased levels of testosterone with elevated follicle stimulating hormone and luteinizing hormone levels in mice exposed to arsenic during early stages of development are indicative of intact pituitary-testicular axis. The results indicate that exposure to arsenic during early stages of development suppresses the male reproduction in adults. Thus, we conclude that the potential of reproduction is programmed, to some extent, in the early stages of development and hence any toxic insult during embryonic development and lactation suppresses male reproductive potential in adulthood.
01 Jan 2012
TL;DR: Investigation revealed that Artesunate caused significant alterations in a dose dependent manner in the testis of male albino mice of Swiss Strain, resulting in a decline in sperm production.
Abstract: Malaria is a global problem with the greatest burden of disease and mortality occurring in tropical and subtropical regions, especially in developing countries. The present study is focused to screen Artesunate toxicity in testis of male albino mice of Swiss Strain. Artesunate is a semi-synthetic water-soluble derivative of artemisinin generally used to treat chloroquine resistant malaria. Oral doses of 150mg/kg.b.wt and 300mg/kg.b.wt were administered for a period of 14, 21 and 45 days. Effects were observed on some specific parameters like 3β hydroxysteroid dehydrogenase, 17β hydroxysteroid dehydrogenase, cholesterol, protein and histology of concerned tissue using standard methods. The results of present investigation revealed that Artesunate caused significant alterations in a dose dependent manner. The histological findings after H&E staining indicated that the treated section of the testis showed some varying degree of cell clustering, cellular hypertrophy and intercellular vacuolations specifically in the germinal cell layer, resulting in a decline in sperm production. The germinal cell nuclei were highly pyknotic. Vacuolization within the interstitium was also observed particularly in the Leydig cell cytoplasm.
TL;DR: A small library of novel non-steroidal and non-chiral 17β-HSD2 inhibitors is designed, synthesized and evaluated in a cell-free assay using human placental microsomal enzyme.
Abstract: A small library of novel non-steroidal and non-chiral 17β-HSD2 inhibitors is designed, synthesized and evaluated in a cell-free assay using human placental microsomal enzyme.
TL;DR: In this article, a series of disubstituted 1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) -a novel and attractive target for the treatment of osteoporosis.
Abstract: A series of disubstituted-1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) - a novel and attractive target for the treatment of osteoporosis. 17βHSD2 catalyzes the oxidation of the highly active estrogen 17β-estradiol (E2) and androgen testosterone (T) into the weak estrone and androstenedione, respectively. Inhibition of this enzyme will locally in the bone lead to an increase in E2 and T levels, two key players in the maintenance of the balance between bone resorption and bone formation. In this study, a new class of 17βHSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17βHSD2 inhibitory activity and a good selectivity toward 17βHSD1. They could be a useful tool to map the unexplored enzyme active site.
01 Jan 2012
TL;DR: Oestrogens play key roles in the development of the majority of breast tumours, a fact that has been exploited successfully in treating breast cancer with tamoxifen, which is a selective oestrogen.
Abstract: Oestrogens play key roles in the development of the majority of breast tumours, a fact that has been exploited successfully in treating breast cancer with tamoxifen, which is a selective oestrogen ...
Journal Article•
TL;DR: The patient, claimed to be a male, presented to us with pubertal gender swing from female to male due to 17β-hydroxysteroid dehydrogenase-3 deficiency and was diagnosed as a case of 46,XY Disorders of Sex Development (DSD).
Abstract: Mymensingh Med J. 2012 Jan;21(1):170-174 The abstract of this article is available on the PubMed website