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CYP17A1

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https://www.readbyqxmd.com/read/27871977/a-time-course-regulatory-and-kinetic-expression-study-of-steroid-metabolizing-enzymes-by-calcitriol-in-primary-cultured-human-placental-cells
#1
Nancy Noyola-Martínez, Ali Halhali, Verónica Zaga-Clavellina, Andrea Olmos-Ortiz, Fernando Larrea, David Barrera
1,25-dihydroxivitamin D3 (calcitriol), is a secoesteroid involved in several placental functions. In particular, we and others showed that calcitriol regulates peptides, proteins, cytokines and hormones production in human trophoblastic cells. On the other hand, calcitriol modifies the activity and expression of some steroidogenic enzymes, a process that is considered tissue-specific. However, the effects of calcitriol on the expression of enzymes involved in the synthesis of sex steroids in placental tissue have not yet been entirely studied...
November 18, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27798284/assessment-of-growth-and-metabolism-characteristics-in-offspring-of-dehydroepiandrosterone-induced-polycystic-ovary-syndrome-adults
#2
Ying Huang, Jiang-Man Gao, Chun-Mei Zhang, Hong-Cui Zhao, Yue Zhao, Rong Li, Yang Yu, Jie Qiao
Polycystic ovary syndrome (PCOS) is a common reproductive disorder that has many characteristic features including hyperandrogenemia, insulin resistance and obesity, which may have significant implications for pregnancy outcomes and long-term health of women. Daughters born to PCOS mothers constitute a high-risk group for metabolic and reproductive derangements, but no report has described potential growth and metabolic risk factors for such female offspring. Hence, we used a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS to study the mechanisms underlying the pathology of PCOS by investigating the growth, developmental characteristics, metabolic indexes and expression profiles of key genes of offspring born to the models...
December 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/27794047/inhibition-of-akr1c3-activation-overcomes-resistance-to-abiraterone-in-advanced-prostate-cancer
#3
Chengfei Liu, Cameron M Armstrong, Wei Lou, Alan Lombard, Christopher P Evans, Allen C Gao
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 re-sensitizes resistant cells to abiraterone treatment...
October 28, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27793677/disordered-zonal-and-cellular-cyp11b2-enzyme-expression-in-familial-hyperaldosteronism-type-3
#4
Celso E Gomez-Sanchez, Xin Qi, Elise P Gomez-Sanchez, Hironobu Sasano, Martin O Bohlen, Max Wisgerhof
Three forms of familial primary aldosteronism have been recognized. Familial Hyperaldosteronism type 1 (FH1) or dexamethasone suppressible hyperaldosteronism, FH2, the most common form of as yet unknown cause(s), and FH3. FH3 is due to activating mutations of the potassium channel gene KCNJ5 that increase constitutive and angiotensin II-induced aldosterone synthesis. In this study we examined the cellular distribution of CYP11B2, CYP11B1, CYP17A1 and KCNJ5 in adrenals from two FH3 siblings using immunohistochemistry and immunofluorescence and obtained unexpected results...
January 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27775788/local-bone-marrow-renin-angiotensin-system-in-the-genesis-of-leukemia-and-other-malignancies
#5
I C Haznedaroglu, U Y Malkan
The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages...
October 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27760586/effects-of-angiogenin-on-granulosa-and-theca-cell-function-in-cattle
#6
J L Dentis, N B Schreiber, A M Burress, L J Spicer
Angiogenin is a member of the ribonuclease A superfamily of proteins that has been implicated in stimulating angiogenesis but whether angiogenin can directly affect ovarian granulosa or theca cell function is unknown. Therefore, the objective of these studies was to determine the effect of angiogenin on proliferation and steroidogenesis of bovine granulosa and theca cells. In experiments 1 and 2, granulosa cells from small (1 to 5 mm diameter) follicles and theca cells from large (8 to 22 mm diameter) follicles were cultured to evaluate the dose-response effect of recombinant human angiogenin on steroidogenesis...
October 20, 2016: Animal: An International Journal of Animal Bioscience
https://www.readbyqxmd.com/read/27754305/lbos-02-06-histopathological-specific-mutation-spectrum-of-aldosterone-producing-adenomas
#7
Elena Azizan, Norlela Sukor, Nor Azmi Kamaruddin, A Rahman A Jamal, Jiri Ceral, Miroslav Solar, Isa Mohamed Rose, Geok Chin Tan
OBJECTIVE: Aldosterone-producing adenoma (APA) is a common curable cause of hypertension. Somatic mutations in five genes (KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1) have been found to cause the excess aldosterone production of two thirds of APAs [1-4]. KCNJ5 mutant APAs, the most common and largest, had explicit genotype-phenotype relationship - a low protein expression of KCNJ5 relative to their peritumoural zona glomerulosa (ZG) and a zona fasciculata-like composition [5-6]. Conversely for the other genes, controversy arises on whether they have the opposite cell phenotype [4,7-8]...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27748439/targeting-of-cyp17a1-lyase-by-vt-464-inhibits-adrenal-and-intratumoral-androgen-biosynthesis-and-tumor-growth-of-castration-resistant-prostate-cancer
#8
Sankar N Maity, Mark A Titus, Revekka Gyftaki, Guanglin Wu, Jing-Fang Lu, S Ramachandran, Elsa M Li-Ning-Tapia, Christopher J Logothetis, John C Araujo, Eleni Efstathiou
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation...
October 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27748298/a-cross-sectional-study-to-assess-any-possible-linkage-of-c-t-polymorphism-in-cyp17a1-gene-with-insulin-resistance-in-non-obese-women-with-polycystic-ovarian-syndrome
#9
Ushasi Banerjee, Anindya Dasgupta, Aparna Khan, Mrinal Kanti Ghosh, Pranab Roy, Jayanta Kumar Rout, Priyankar Roy, Suparna Dhara
BACKGROUND & OBJECTIVES: Insulin resistance (IR) is a major confounding factor in polycystic ovarian syndrome (PCOS) irrespective of obesity. Its exact mechanism remains elusive till now. C/T polymorphism in the -34 promoter region of the CYP17 gene is inconsistently attributed to elucidate the mechanism of IR and its link to hyperandrogenemia in obese PCOS patients. In the present study we aimed to evaluate any association of this polymorphism with IR in non-obese women with PCOS. METHODS: Polymorphism study was performed by restriction fragment length polymorphism (RFLP) analysis of the Msp A1 digest of the PCR product of the target gene in 75 PCOS cases against 73 age and BMI matched control women...
June 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27706926/discordant-genotyping-results-using-dna-isolated-from-anti-doping-control-urine-samples
#10
Eva Choong, Jenny J Schulze, Magnus Ericsson, Anders Rane, Lena Ekström
The UGT2B17 gene deletion polymorphism is known to correlate to urinary concentration of testosterone-glucuronide and hence this genotype exerts a large impact on the testosterone/epitestosterone (T/E) ratio, a biomarker for testosterone doping. The objective of this study was to assess if DNA isolated from athletes' urine samples (n = 713) obtained in routine doping controls could be targeted for genotyping analysis for future integration in the athlete's passport. A control population (n = 21) including both urine and blood DNA was used for genotyping concordance test...
October 5, 2016: Drug Testing and Analysis
https://www.readbyqxmd.com/read/27683267/effects-of-daily-exposure-to-saccharin-and-sucrose-on-testicular-biologic-functions-in-mice
#11
Ting Gong, Quan-Wei Wei, Da-Gan Mao, Kentaro Nagaoka, Gen Watanabe, Kazuyoshi Taya, Fang-Xiong Shi
Saccharin sodium consumption is considered safe and beneficial, owing to its very intense sweetness without any associated calories, but supporting scientific data remain sparse and controversial. Herein, we demonstrate that dose-response relationships existed with regard to administration of saccharin or sucrose to mice for 35 days, and this association involved testis-expressed sweet-tasting molecules (taste receptor type 1 subunit 3 [T1R3]; G protein alpha-gustducin [Galpha]). Mouse body weights and testis weights in middle- and low-dose saccharin-treated groups were increased with up-expressions of molecules involved in testicular sweet taste and steroidogenic (middle saccharin: steroidogenic acute regulatory protein [StAR]; P450 cholesterol side-chain cleavage enzyme [CYP11A1]; 17-alpha-hydroxylase/C17,20-lyase [CYP17A1]; low saccharin: StAR)...
December 2016: Biology of Reproduction
https://www.readbyqxmd.com/read/27683182/a-phase-ii-trial-of-abiraterone-combined-with-dutasteride-for-men-with-metastatic-castration-resistant-prostate-cancer
#12
Mary-Ellen Taplin, Rana R McKay, Lillian Werner, Elahe A Mostaghel, Rosina T Lis, Olga Voznesensky, Zhenwei Zhang, Brett Marck, Alvin M Matsumoto, Liran Domachevsky, Katherine A Zukotynski, Manoj K Bhasin, Glenn J Bubley, Bruce Montgomery, Philip W Kantoff, Steven P Balk
PURPOSE: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. EXPERIMENTAL DESIGN: Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27643307/lbos-02-06-histopathological-specific-mutation-spectrum-of-aldosterone-producing-adenomas
#13
Elena Azizan, Norlela Sukor, Nor Azmi Kamaruddin, A Rahman A Jamal, Jiri Ceral, Miroslav Solar, Isa Mohamed Rose, Geok Chin Tan
OBJECTIVE: Aldosterone-producing adenoma (APA) is a common curable cause of hypertension. Somatic mutations in five genes (KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1) have been found to cause the excess aldosterone production of two thirds of APAs [1-4]. KCNJ5 mutant APAs, the most common and largest, had explicit genotype-phenotype relationship - a low protein expression of KCNJ5 relative to their peritumoural zona glomerulosa (ZG) and a zona fasciculata-like composition [5-6]. Conversely for the other genes, controversy arises on whether they have the opposite cell phenotype [4,7-8]...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27583544/influence-of-statins-on-survival-outcome-in-patients-with-metastatic-castration-resistant-prostate-cancer-treated-with-abiraterone-acetate
#14
Martin Boegemann, Katrin Schlack, Ann-Kathrin Fischer, Joachim Gerß, Julie Steinestel, Axel Semjonow, Andres Jan Schrader, Laura-Maria Krabbe
OBJECTIVE: Even though the exact mechanism is largely unknown until now, statins are supposed to improve survival outcomes in various malignancies. For prostate cancer however, statins are known to compete with dehydroepiandrosterone (DHEAS) for the transport into the cytosol both using the cell by the Solute Carrier Transporter and thus diminish the cellular uptake of DHEAS as a precursor of androgens. Abiraterone inhibits CYP17A1 and thus effectively decreases the production of all relevant androgens including DHEAS...
2016: PloS One
https://www.readbyqxmd.com/read/27571716/effects-of-azocyclotin-on-gene-transcription-and-steroid-metabolome-of-hypothalamic-pituitary-gonad-axis-and-their-consequences-on-reproduction-in-zebrafish-danio-rerio
#15
You-Ning Ma, Chu-Yan Cao, Qiang-Wei Wang, Wen-Jun Gui, Guo-Nian Zhu
The widely used organotins have the potential to disrupt the endocrine system, but little is known of underlying mechanisms of azocyclotin toxicity in fish. The objective of the present study was to investigate the impact of azocyclotin on reproduction in zebrafish. Adult zebrafish were exposed to 0.09 and 0.45μg/L azocyclotin for 21days, and effects on steroid hormones and mRNA expression of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. Mass spectrometry methodology was developed to profile steroids within the metabolome of the gonads...
October 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/27566228/structural-insights-into-the-function-of-steroidogenic-cytochrome-p450-17a1
#16
REVIEW
Rahul Yadav, Elyse M Petrunak, D Fernando Estrada, Emily E Scott
Cytochrome P450 17A1 (CYP17A1) operates at the core of human steroidogenesis, directing precursors into mineralocorticoids, glucocorticoids, or sex steroids. Although the 17α-hydroxylase and 17,20-lyase activities of this dual function enzyme have been investigated extensively, until recently no CYP17A1 structures were available to inform our understanding. Structures of CYP17A1 with a range of steroidal inhibitors and substrates are now available. This review relates functional knowledge of this enzyme to structural features defining the selective differentiation between its various substrates...
August 24, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27557496/dual-targeting-of-androgen-receptor-and-mtorc1-by-salinomycin-in-prostate-cancer
#17
Nooshin Mirkheshti, Sulgi Park, Shoulei Jiang, Jodie Cropper, Sherry L Werner, Chung S Song, Bandana Chatterjee
Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors...
August 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27505042/oxazolinyl-derivatives-of-17-20-e-21-norpregnene-differing-in-the-structure-of-a-and-b-rings-facile-synthesis-and-inhibition-of-cyp17a1-catalytic-activity
#18
Vladimir A Kostin, Vladimir A Zolottsev, Alexey V Kuzikov, Rami A Masamrekh, Victoria V Shumyantseva, Alexander V Veselovsky, Sergey V Stulov, Roman A Novikov, Vladimir P Timofeev, Alexander Y Misharin
Five 4,5-dihydro-1,3-oxazole derivatives of [17(20)E]-21-norpregnene, comprising 3β-hydroxy-5-ene (1), 3,6-dioxo-4-ene (2), 3-oxo-4-ene (3), 3α,5α-cyclo-6-oxo (4), 3β-hydroxy-6-oxo (5) fragments were synthesized. Synthesis was conducted with improved procedure, based on reaction of suitably protected [17(20)E]-pregnen-21-oic acids with ethanolamine in presence of triphenyl phosphine, carbon tetrachloride, and triethyl amine. Potency of the compounds 1-5 to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity was studied by highly sensitive electrochemical method, using the enzyme immobilization technique...
November 2016: Steroids
https://www.readbyqxmd.com/read/27465829/endogenous-inhibins-regulate-steroidogenesis-in-mouse-tm3-leydig-cells-by-altering-smad2-signalling
#19
Yao Wang, Maree Bilandzic, Guck T Ooi, Jock K Findlay, Kaye L Stenvers
This study tested the hypothesis that inhibins act in an autocrine manner on Leydig cells using a pre-pubertal Leydig cell line, TM3, as a model of immature Leydig cells. The expression of Inha, Inhba, and Inhbb in TM3 cells was determined by RT-PCR and the production of the inhibin-alpha subunit was confirmed by western blot. Knockdown of Inha expression resulted in significant decreases in the expression of Leydig cell markers Cyp17a1, Cyp11a1, Nr5a1, and Insl3. Western blot showed that activin A, TGFβ1 and TGFβ2 activated SMAD2, and that knockdown of Inha expression in TM3 cells enhanced both activin A- and TGFβ-induced SMAD2 activation...
November 15, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27435344/hedgehog-proteins-consume-steroidal-cyp17a1-antagonists-potential-therapeutic-significance-in-advanced-prostate-cancer
#20
Brandon M Bordeau, Daniel A Ciulla, Brian P Callahan
Abiraterone, a potent inhibitor of the human enzyme CYP17A1 (cytochrome P450c17), provides a last line of defense against ectopic androgenesis in advanced prostate cancer. Herein we report an unprecedented off-target interaction between abiraterone and oncogenic hedgehog proteins. Our experiments indicate that abiraterone and its structural congener, galeterone, can replace cholesterol as a substrate in a specialized biosynthetic event of hedgehog proteins, known as cholesterolysis. The off-target reaction generates covalent hedgehog-drug conjugates...
September 20, 2016: ChemMedChem
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