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[PMID]:29372682
[Au] Autor:Kmetová Sivonová M; Jureceková J; Tatarková Z; Kaplán P; Lichardusová L; Hatok J
[Ad] Endereço:Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. sivonova@jfmed.uniba.sk.
[Ti] Título:The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition.
[So] Source:Gen Physiol Biophys;36(5):487-499, 2017 Dec.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Androgens play an important role during the development of both normal prostate epithelium and prostate cancer and variants of genes involved in androgen metabolism may be related to an increased risk of prostate disease. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a key regulatory enzyme in the steroidogenic pathway; it catalyses both 17α-hydroxylase and 17,20-lyase activities and is essential for the production of both androgens and glucocorticoids. In this review, we focus on the structure and enzymatic activity of CYP17A1 and the mechanism of modulation of CYP17A1 activities. We discuss the relationship between common genetic variations in CYP17A1 gene and prostate cancer risk and the main effects of these variations on the prediction of susceptibility and clinical outcomes of prostate cancer patients. The mechanism of action, the efficacy and the clinical potential of CYP17A1 inhibitors in prostate cancer are also summarized.
[Mh] Termos MeSH primário: Androgênios/metabolismo
Glucocorticoides/metabolismo
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Esteroide 17-alfa-Hidroxilase/genética
Esteroide 17-alfa-Hidroxilase/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores Tumorais/química
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Marcadores Genéticos/genética
Predisposição Genética para Doença/genética
Seres Humanos
Masculino
Modelos Biológicos
Neoplasias da Próstata/tratamento farmacológico
Esteroide 17-alfa-Hidroxilase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Androgens); 0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Glucocorticoids); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2017024


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[PMID]:27773742
[Au] Autor:Mahalingam S; Gao L; Eisner J; Helferich W; Flaws JA
[Ad] Endereço:Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802, United States. Electronic address: mahalin2@illinois.edu.
[Ti] Título:Effects of isoliquiritigenin on ovarian antral follicle growth and steroidogenesis.
[So] Source:Reprod Toxicol;66:107-114, 2016 12.
[Is] ISSN:1873-1708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Isoliquiritigenin is a botanical estrogen used as a dietary supplement. Previous studies show that other botanical estrogens affect ovarian estradiol synthesis, but isoliquiritigenin's effects on the ovary are unknown. Thus, this study tested the hypothesis that isoliquiritigenin inhibits ovarian antral follicle growth and steroidogenesis. Antral follicles from CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or isoliquiritigenin (0.6µM, 6 µM, 36 µM, and 100 µM) for 48-96h. During culture, follicle diameters were measured daily to assess follicle growth. After culture, media were collected for hormone assays and follicles were collected for gene expression analysis of steroidogenic enzymes. Isoliquiritigenin inhibited antral follicle growth and altered estradiol, testosterone, and progesterone levels. Additionally, isoliquiritigenin altered the mRNA levels of cytochrome P450 steroid 17-α-hydroxylase 1, aromatase, 17ß-hydroxysteroid dehydrogenase 1, and steroidogenic acute regulatory protein. These data indicate that exposure to isoliquiritigenin inhibits growth and disrupts steroid production in antral follicles.
[Mh] Termos MeSH primário: Chalconas/toxicidade
Folículo Ovariano/efeitos dos fármacos
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
Animais
Aromatase/genética
Estradiol/metabolismo
Feminino
Camundongos
Folículo Ovariano/crescimento & desenvolvimento
Folículo Ovariano/metabolismo
Fosfoproteínas/genética
Progesterona/metabolismo
RNA Mensageiro/metabolismo
Esteroide 17-alfa-Hidroxilase/genética
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Chalcones); 0 (Phosphoproteins); 0 (RNA, Messenger); 0 (steroidogenic acute regulatory protein); 3XMK78S47O (Testosterone); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); B9CTI9GB8F (isoliquiritigenin); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (hydroxysteroid (17-beta) dehydrogenase 1, mouse); EC 1.14.14.1 (Aromatase); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29045471
[Au] Autor:Robiou-du-Pont S; Anand SS; Morrison KM; McDonald SD; Atkinson SA; Teo KK; Meyre D
[Ad] Endereço:Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
[Ti] Título:Parental and offspring contribution of genetic markers of adult blood pressure in early life: The FAMILY study.
[So] Source:PLoS One;12(10):e0186218, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous genome wide association studies (GWAS) identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs) for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) study followed-up for 5 years. Two genotype scores for systolic (29 SNPs) and diastolic (24 SNPs) blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in CSK and systolic blood pressure (ß = 0.98±0.46, P = 3.4×10-2). The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (CYP17A1) (paternal, ß = 2.78±1.49, P = 6.1×10-2 for SBP and ß = 3.60±1.24, P = 3.7×10-3 for DBP), rs17367504 (MTHFR) (paternal, ß = 2.42±0.93, P = 9.3×10-3 for SBP and ß = 1.89±0.80, P = 1.8×10-2 for DBP and maternal, ß = -1.32±0.60, P = 2.9×10-2 and ß = -1.97±0.77, P = 1.0×10-2, for SBP and DBP respectively) and child blood pressure. Our study supports the view that adult GWAS loci have a limited impact on blood pressure during the five first years of life. The parental genetic effects observed on blood pressure in children may suggest epigenetic mechanisms in the transmission of the risk of hypertension. Further replication is needed to confirm our results.
[Mh] Termos MeSH primário: Pressão Sanguínea/genética
Hipertensão/genética
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética
Esteroide 17-alfa-Hidroxilase/genética
Quinases da Família src/genética
[Mh] Termos MeSH secundário: Adulto
Pré-Escolar
Feminino
Marcadores Genéticos
Estudo de Associação Genômica Ampla
Seres Humanos
Hipertensão/fisiopatologia
Lactente
Masculino
Polimorfismo de Nucleotídeo Único
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Genetic Markers); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.5.1.20 (MTHFR protein, human); EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2)); EC 2.7.10.2 (CSK tyrosine-protein kinase); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171019
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186218


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[PMID]:28893623
[Au] Autor:Malikova J; Brixius-Anderko S; Udhane SS; Parween S; Dick B; Bernhardt R; Pandey AV
[Ad] Endereço:Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Inselspital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
[Ti] Título:CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21-hydroxylase activity of CYP21A2.
[So] Source:J Steroid Biochem Mol Biol;174:192-200, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary results, we had observed inhibition of CYP21A2 by 1µM abiraterone. Here we are reporting the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone for 24h and CYP21A2 activity was measured using [ H] 17-hydroxyprogesterone as substrate. Whole steroid profile changes were determined by gas chromatography-mass spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured spectroscopically. Computational docking was used to study the binding and interaction of abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in assays with cells and an inhibition of CYP21A2 activity was also observed in experiments using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 6.3µM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could result in lower cortisol levels and may require monitoring for any potential adverse effects.
[Mh] Termos MeSH primário: Androstenos/farmacologia
Antineoplásicos/farmacologia
Esteroide 21-Hidroxilase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Escherichia coli/genética
Seres Humanos
Masculino
Simulação de Acoplamento Molecular
Neoplasias da Próstata
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
Esteroide 21-Hidroxilase/química
Esteroide 21-Hidroxilase/genética
Esteroide 21-Hidroxilase/metabolismo
Esteroides/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenes); 0 (Antineoplastic Agents); 0 (Steroids); EC 1.14.14.16 (CYP21A2 protein, human); EC 1.14.14.16 (Steroid 21-Hydroxylase); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); G819A456D0 (abiraterone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


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[PMID]:28890368
[Au] Autor:de Mello Martins AGG; Allegretta G; Unteregger G; Haupenthal J; Eberhard J; Hoffmann M; van der Zee JA; Junker K; Stöckle M; Müller R; Hartmann RW; Ohlmann CH
[Ad] Endereço:Department of Drug Design and Optimization (DDOP), Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8.1, 66123 Saarbrücken, Germany.
[Ti] Título:CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3ß,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone.
[So] Source:J Steroid Biochem Mol Biol;174:183-191, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5α-pregnan-3ß,6α-diol-20-one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Δ -Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen-responsive cells. Our results demonstrate the CYP17A1-independent formation of 5α-pregnan-3ß,6α-diol-20-one by androgen-responsive prostate cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated.
[Mh] Termos MeSH primário: Pregnanolona/análogos & derivados
Neoplasias da Próstata/metabolismo
Esteroide 17-alfa-Hidroxilase/metabolismo
[Mh] Termos MeSH secundário: Androgênios/metabolismo
Androstenos/farmacologia
Linhagem Celular Tumoral
Hormônios Esteroides Gonadais/metabolismo
Seres Humanos
Masculino
Pregnanolona/metabolismo
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Androstenes); 0 (Gonadal Steroid Hormones); 570-78-5 (pregnan-3,6-diol-20-one); BXO86P3XXW (Pregnanolone); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); G819A456D0 (abiraterone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


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[PMID]:28831954
[Au] Autor:Xu H; Cao L; Wei Y; Zhang Y; Liang M
[Ad] Endereço:1Yellow Sea Fisheries Research Institute,Chinese Academy of Fishery Sciences,106 Nanjing Road,Qingdao 266071,People's Republic of China.
[Ti] Título:Effects of different dietary DHA:EPA ratios on gonadal steroidogenesis in the marine teleost, tongue sole (Cynoglossus semilaevis).
[So] Source:Br J Nutr;118(3):179-188, 2017 Aug.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The present study was conducted to investigate the effects of dietary DHA and EPA on gonadal steroidogenesis in mature females and males, with a feeding trial on tongue sole, a typical marine teleost with sexual dimorphism. Three experimental diets differing basically in DHA:EPA ratio, that is, 0·68 (diet D:E-0·68), 1·09 (D:E-1·09) and 2·05 (D:E-2·05), were randomly assigned to nine tanks of 3-year-old tongue sole (ten females and fifteen males in each tank). The feeding trail lasted for 90 d before and during the spawning season. Fish were reared in a flowing seawater system and fed to apparent satiation twice daily. Compared with diet D:E-0·68, diet D:E-1·09 significantly enhanced the oestradiol production in females, whereas diet D:E-2·05 significantly enhanced the testosterone production in males. In ovaries, diet D:E-1·09 induced highest mRNA expression of follicle-stimulating hormone receptor (FSHR), steroidogenic acute regulatory protein, 17α-hydroxylase (P450c17) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD). In testes, diet 2·05 resulted in highest mRNA expression of FSHR, cholesterol side-chain cleavage enzyme, P450c17 and 3ß-HSD. Fatty acid profiles in fish tissues reflected closely those of diets. Female fish had more gonadal EPA content but less DHA content than male fish, whereas there was a reverse observation in liver. In conclusion, the dietary DHA:EPA ratio, possibly combined with the dietary EPA:arachidonic acid ratio, differentially regulated sex steroid hormone synthesis in mature female and male tongue soles. Females seemed to require more EPA but less DHA for the gonadal steroidogenesis than males. The results are beneficial to sex-specific nutritive strategies in domestic teleost.
[Mh] Termos MeSH primário: Dieta/veterinária
Ácidos Docosa-Hexaenoicos/administração & dosagem
Ácido Eicosapentaenoico/administração & dosagem
Linguados/metabolismo
Hormônios Esteroides Gonadais/biossíntese
Gônadas/efeitos dos fármacos
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
17-Hidroxiesteroide Desidrogenases/metabolismo
Animais
Ácido Araquidônico/administração & dosagem
Ácido Araquidônico/análise
Ácidos Docosa-Hexaenoicos/análise
Ácido Eicosapentaenoico/análise
Estradiol/biossíntese
Estradiol/sangue
Feminino
Hormônios Esteroides Gonadais/sangue
Gônadas/metabolismo
Lipogênese/efeitos dos fármacos
Masculino
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptores do FSH/genética
Receptores do FSH/metabolismo
Esteroide 17-alfa-Hidroxilase/genética
Esteroide 17-alfa-Hidroxilase/metabolismo
Testosterona/biossíntese
Testosterona/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Gonadal Steroid Hormones); 0 (RNA, Messenger); 0 (Receptors, FSH); 25167-62-8 (Docosahexaenoic Acids); 27YG812J1I (Arachidonic Acid); 3XMK78S47O (Testosterone); 4TI98Z838E (Estradiol); AAN7QOV9EA (Eicosapentaenoic Acid); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517001891


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[PMID]:28697343
[Au] Autor:Small EJ
[Ad] Endereço:University of California, San Francisco, CA, USA. Electronic address: eric.small@ucsf.edu.
[Ti] Título:Redefining Hormonal Therapy for Advanced Prostate Cancer: Results from the LATITUDE and STAMPEDE Studies.
[So] Source:Cancer Cell;32(1):6-8, 2017 07 10.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation.
[Mh] Termos MeSH primário: Acetato de Abiraterona/uso terapêutico
Antineoplásicos/uso terapêutico
Neoplasias da Próstata/tratamento farmacológico
[Mh] Termos MeSH secundário: Resistência a Medicamentos Antineoplásicos
Seres Humanos
Masculino
Neoplasias da Próstata/patologia
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EM5OCB9YJ6 (Abiraterone Acetate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE


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[PMID]:28692125
[Au] Autor:Dos Santos EVW; Alves LNR; Louro ID
[Ad] Endereço:Núcleo de Genética Humana e Molecular Departamento de Ciências Biológicas, Centro de Ciências Humanas e Naturais, , , Brasil eldamariavw@yahoo.com.br.
[Ti] Título:Steroid metabolism gene polymorphisms and their implications on breast and ovarian cancer prognosis.
[So] Source:Genet Mol Res;16(3), 2017 Jul 06.
[Is] ISSN:1676-5680
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:A role for estrogen in the etiology of breast and ovarian cancers has been suggested; therefore, genetic polymorphisms in steroid metabolism genes could be involved in the carcinogenesis of these tumors. We have aimed to investigate the role of GSTP1 and CYP17 polymorphisms and their correlation with MSI (microsatellite instability) and LOH (loss of heterozygosity) in AR, ERß and CYP19 genes in women from Espírito Santo State, Brazil. The study population consisted of 107 female breast and 24 ovarian tumors. GSTP1 and CYP17 polymorphisms were detected by polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP) analysis while MSI and LOH were analyzed by PCR. GSTP1 and CYP17 polymorphisms alone were not associated with an increased risk for breast or ovarian tumors. However, when combined with MSI/LOH in AR, ERß and CYP19 genes, we were able to detect significant associations with the GSTP1 wild-type genotype in PR (progesterone receptor) negative breast cancers or the CYP17 wild-type genotype in ER (estrogen receptor) and PR-negative breast tumors. No associations with ovarian tumors were detected. Our results suggest that wild-type GSTP1 or CYP17 genes when combined with LOH/MSI in steroid metabolism genes may play a role in ER and/or PR negative breast cancers. These data support the hypothesis that genes related to steroid metabolism are important in the characterization of breast cancer and that the analysis of single polymorphisms may not be sufficient.
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Glutationa S-Transferase pi/genética
Neoplasias Ovarianas/genética
Polimorfismo Genético
Esteroide 17-alfa-Hidroxilase/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Neoplasias da Mama/patologia
Feminino
Seres Humanos
Perda de Heterozigosidade
Repetições de Microssatélites
Meia-Idade
Neoplasias Ovarianas/patologia
Esteroides/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Steroids); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 2.5.1.18 (GSTP1 protein, human); EC 2.5.1.18 (Glutathione S-Transferase pi)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.4238/gmr16039691


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[PMID]:28684414
[Au] Autor:Gonzalez E; Guengerich FP
[Ad] Endereço:From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
[Ti] Título:Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1.
[So] Source:J Biol Chem;292(32):13168-13185, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 (P450, CYP) 17A1 plays a critical role in steroid metabolism, catalyzing both the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17α,20-lyase reactions to form dehydroepiandrosterone (DHEA) and androstenedione (Andro), respectively, critical for generating glucocorticoids and androgens. Human P450 17A1 reaction rates examined are enhanced by the accessory protein cytochrome ( ), but the exact role of in P450 17A1-catalyzed reactions is unclear as are several details of these reactions. Here, we examined in detail the processivity of the 17α-hydroxylation and lyase steps. did not enhance reaction rates by decreasing the rates of any of the steroids. Steroid binding to P450 17A1 was more complex than a simple two-state system. Pre-steady-state experiments indicated lag phases for Andro production from progesterone and for DHEA from pregnenolone, indicating a distributive character of the enzyme. However, we observed processivity in pregnenolone/DHEA pulse-chase experiments. ( )-Orteronel was three times more inhibitory toward the conversion of 17α-hydroxypregnenolone to DHEA than toward the 17α-hydroxylation of pregnenolone. IC values for ( )-orteronel were identical for blocking DHEA formation from pregnenolone and for 17α-hydroxylation, suggestive of processivity. Global kinetic modeling helped assign sets of rate constants for individual or groups of reactions, indicating that human P450 17A1 is an inherently distributive enzyme but that some processivity is present, some of the 17α-OH pregnenolone formed from pregnenolone did not dissociate from P450 17A1 before conversion to DHEA. Our results also suggest multiple conformations of P450 17A1, as previously proposed on the basis of NMR spectroscopy and X-ray crystallography.
[Mh] Termos MeSH primário: 17-alfa-Hidroxipregnenolona/metabolismo
Citocromos b5/metabolismo
Desidroepiandrosterona/metabolismo
Modelos Moleculares
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Pregnenolona/metabolismo
Esteroide 17-alfa-Hidroxilase/metabolismo
[Mh] Termos MeSH secundário: 17-alfa-Hidroxipregnenolona/química
Androstenodiona/química
Androstenodiona/metabolismo
Animais
Sítios de Ligação
Biocatálise/efeitos dos fármacos
Inibidores das Enzimas do Citocromo P-450/química
Inibidores das Enzimas do Citocromo P-450/metabolismo
Inibidores das Enzimas do Citocromo P-450/farmacologia
Citocromos b5/genética
Desidroepiandrosterona/química
Seres Humanos
Imidazóis/química
Imidazóis/metabolismo
Imidazóis/farmacologia
Cinética
Ligantes
NADPH-Ferri-Hemoproteína Redutase/genética
Naftalenos/química
Naftalenos/metabolismo
Naftalenos/farmacologia
Oxirredução
Pregnenolona/química
Progesterona/química
Progesterona/metabolismo
Conformação Proteica
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Estereoisomerismo
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
Esteroide 17-alfa-Hidroxilase/química
Esteroide 17-alfa-Hidroxilase/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CYB5A protein, human); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Imidazoles); 0 (Ligands); 0 (Naphthalenes); 0 (Recombinant Proteins); 387-79-1 (17-alpha-Hydroxypregnenolone); 409J2J96VR (Androstenedione); 459AG36T1B (Dehydroepiandrosterone); 4G7DS2Q64Y (Progesterone); 73R90F7MQ8 (Pregnenolone); 9035-39-6 (Cytochromes b5); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); UE5K2FNS92 (orteronel)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.794917


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[PMID]:28648378
[Au] Autor:Alyamani M; Li Z; Berk M; Li J; Tang J; Upadhyay S; Auchus RJ; Sharifi N
[Ad] Endereço:Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
[Ti] Título:Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities.
[So] Source:Cell Chem Biol;24(7):825-832.e6, 2017 Jul 20.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ ,3ß-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3ß-hydroxysteroid dehydrogenase (3ßHSD). We found that galeterone is metabolized by 3ßHSD to Δ -galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3ß-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5ß-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ ,3ß-hydroxyl structure.
[Mh] Termos MeSH primário: Androstadienos/metabolismo
Benzimidazóis/metabolismo
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
17-Hidroxiesteroide Desidrogenases/metabolismo
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
Androstadienos/análise
Androstadienos/uso terapêutico
Animais
Benzimidazóis/análise
Benzimidazóis/uso terapêutico
Linhagem Celular Tumoral
Cromatografia Líquida de Alta Pressão
Células HEK293
Seres Humanos
Hidroxiesteroide Desidrogenases/genética
Hidroxiesteroide Desidrogenases/metabolismo
Estimativa de Kaplan-Meier
Masculino
Camundongos
Pregnenolona/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/mortalidade
Neoplasias da Próstata/patologia
Receptores Androgênicos/genética
Receptores Androgênicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
Esteroide 17-alfa-Hidroxilase/metabolismo
Espectrometria de Massas em Tandem
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstadienes); 0 (Benzimidazoles); 0 (Receptors, Androgen); 73R90F7MQ8 (Pregnenolone); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.357 (AKR1C2 protein, human); EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase); WA33E149SW (3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE



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