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Pesquisa : D08.811.682.047.820.125 [Categoria DeCS]
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[PMID]:28871815
[Au] Autor:Alshogran OY
[Ad] Endereço:a Department of Clinical Pharmacy, Faculty of Pharmacy , Jordan University of Science and Technology , Irbid , Jordan.
[Ti] Título:Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes.
[So] Source:Expert Opin Drug Metab Toxicol;13(10):1063-1073, 2017 Oct.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/genética
Variação Genética
Farmacogenética
[Mh] Termos MeSH secundário: Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética
Predisposição Genética para Doença
Seres Humanos
Preparações Farmacêuticas/metabolismo
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1376648


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[PMID]:28259989
[Au] Autor:Shiiba M; Yamagami H; Yamamoto A; Minakawa Y; Okamoto A; Kasamatsu A; Sakamoto Y; Uzawa K; Takiguchi Y; Tanzawa H
[Ad] Endereço:Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
[Ti] Título:Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity.
[So] Source:Oncol Rep;37(4):2025-2032, 2017 Apr.
[Is] ISSN:1791-2431
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)-resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/biossíntese
3-Hidroxiesteroide Desidrogenases/biossíntese
Hidroxiprostaglandina Desidrogenases/biossíntese
Hidroxiesteroide Desidrogenases/biossíntese
Ácido Mefenâmico/administração & dosagem
Neoplasias/tratamento farmacológico
[Mh] Termos MeSH secundário: 20-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
20-Hidroxiesteroide Desidrogenases/genética
3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
3-Hidroxiesteroide Desidrogenases/genética
Membro C3 da Família 1 de alfa-Ceto Redutase
Cisplatino/administração & dosagem
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Fluoruracila/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células HeLa
Seres Humanos
Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores
Hidroxiprostaglandina Desidrogenases/genética
Hidroxiesteroide Desidrogenases/antagonistas & inibidores
Hidroxiesteroide Desidrogenases/genética
Neoplasias/genética
Neoplasias/patologia
Oxirredutases
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
367589PJ2C (Mefenamic Acid); EC 1.- (Oxidoreductases); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C2 protein, human); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3); EC 1.3.1.20 (trans-1,2-dihydrobenzene-1,2-diol dehydrogenase); Q20Q21Q62J (Cisplatin); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170306
[St] Status:MEDLINE
[do] DOI:10.3892/or.2017.5480


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[PMID]:27436769
[Au] Autor:Robic A; Feve K; Louveau I; Riquet J; Prunier A
[Ad] Endereço:INRA, UMR1388-GenPhySE, Castanet Tolosan, France.
[Ti] Título:Exploration of steroidogenesis-related genes in testes, ovaries, adrenals, liver and adipose tissue in pigs.
[So] Source:Anim Sci J;87(8):1041-7, 2016 Aug.
[Is] ISSN:1740-0929
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:To explore the metabolism of steroids in the pig species, a qualitative PCR analysis was performed for the main transcript of 27 genes involved in steroid metabolism. We compared samples of testes, adipose tissue and liver from immature and peripubertal males, adrenal cortex from peripubertal males, ovaries from cyclic females and adipose tissue from peripubertal females. Some genes were shown to have a tissue-specific expression. Two of them were expressed only in testes, ovaries and adrenals: CYP11A1 and CYP11B. The CYP21 and HSD17B3 genes, were expressed respectively only in adrenals and only in testes. Very few differences were observed between transcriptional patterns of peripubertal testes and adrenal glands as well as between male and female fat tissues. However, the expression of genes involved in the sulfonation of steroids was higher in testes than in adrenals from males. Main differences between ovaries and testes were observed for HSD17B1/2/3, AKR1C-pig6 and sulfotransferase genes (SULT2A1/SULT2B1). The present study shows that the SRD5A2 and CYP21 genes were not involved in the testicular biosynthesis of androstenone. It also shows that porcine adrenal glands produce essentially corticosteroids and that fat tissue is unable to produce de novo steroids.
[Mh] Termos MeSH primário: Tecido Adiposo/metabolismo
Glândulas Suprarrenais/metabolismo
Regulação Enzimológica da Expressão Gênica
Expressão Gênica
Fígado/metabolismo
Ovário/metabolismo
Esteroides/biossíntese
Suínos/genética
Suínos/metabolismo
Testículo/metabolismo
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
17-Hidroxiesteroide Desidrogenases/metabolismo
20-Hidroxiesteroide Desidrogenases/genética
20-Hidroxiesteroide Desidrogenases/metabolismo
Animais
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética
Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo
Família 21 do Citocromo P450/genética
Família 21 do Citocromo P450/metabolismo
Feminino
Masculino
Especificidade de Órgãos/genética
Esteroide 11-beta-Hidroxilase/genética
Esteroide 11-beta-Hidroxilase/metabolismo
Sulfotransferases/genética
Sulfotransferases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Steroids); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 1.14.14.16 (Cytochrome P450 Family 21); EC 1.14.15.4 (Steroid 11-beta-Hydroxylase); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme); EC 2.8.2.- (Sulfotransferases); EC 2.8.2.2 (alcohol sulfotransferase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170316
[Lr] Data última revisão:
170316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160721
[St] Status:MEDLINE
[do] DOI:10.1111/asj.12532


  4 / 398 MEDLINE  
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[PMID]:26824415
[Au] Autor:Wang Y; Wang Y; Zhang Z; Park JY; Guo D; Liao H; Yi X; Zheng Y; Zhang D; Chambers SK; Zheng W
[Ad] Endereço:Department of Obstetrics and Gynecology, Henan Province People's Hospital, Zhengzhou, China.
[Ti] Título:Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway.
[So] Source:Oncotarget;7(9):10363-72, 2016 Mar 01.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Progestin resistance is a main obstacle for endometrial precancer/cancer conservative therapy. Therefore, biomarkers to predict progestin resistance and studies to gain a more detailed understanding of the mechanism are needed. The antioxidant Nrf2-AKR1C1 signal pathway exerts chemopreventive activity. However whether it plays a role in progestin resistance has not been explored. In this study, elevated levels of AKR1C1 and Nrf2 were found in progestin-resistant endometrial epithelia, but not in responsive endometrial glands. Exogenous overexpression of Nrf2/AKR1C1 resulted in progestin resistance. Inversely, silencing of Nrf2 or AKR1C1 rendered endometrial cancer cells more susceptible to progestin treatment. Moreover, medroxyprogesterone acetate withdrawal resulted in suppression of Nrf2/AKR1C1 expression accompanied by a reduction of cellular proliferative activity. In addition, brusatol and metformin overcame progestin resistance by down-regulating Nrf2/AKR1C1 expression. Our findings suggest that overexpression of Nrf2 and AKR1C1 in endometrial precancer/cancer may be part of the molecular mechanisms underlying progestin resistance. If validated in a larger cohort, overexpression of Nrf2 and AKR1C1 may prove to be useful biomarkers to predict progestin resistance. Targeting the Nrf2/AKR1C1 pathway may represent a new therapeutic strategy for treatment of endometrial hyperplasia/cancer.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/metabolismo
Resistência a Medicamentos Antineoplásicos/fisiologia
Neoplasias do Endométrio/tratamento farmacológico
Neoplasias do Endométrio/patologia
Fator 2 Relacionado a NF-E2/metabolismo
Progestinas/uso terapêutico
[Mh] Termos MeSH secundário: 20-Hidroxiesteroide Desidrogenases/genética
Antineoplásicos Hormonais/farmacologia
Biomarcadores Tumorais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Endométrio/metabolismo
Feminino
Seres Humanos
Acetato de Medroxiprogesterona/farmacologia
Metformina/farmacologia
Fator 2 Relacionado a NF-E2/genética
Quassinas/farmacologia
Interferência de RNA
RNA Interferente Pequeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 0 (Biomarkers, Tumor); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Progestins); 0 (Quassins); 0 (RNA, Small Interfering); 14907-98-3 (brusatol); 9100L32L2N (Metformin); C2QI4IOI2G (Medroxyprogesterone Acetate); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160130
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.7004


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[PMID]:26596239
[Au] Autor:Penning TM
[Ad] Endereço:Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, United States. Electronic address: penning@upenn.edu.
[Ti] Título:Single-molecule enzymology of steroid transforming enzymes: Transient kinetic studies and what they tell us.
[So] Source:J Steroid Biochem Mol Biol;161:5-12, 2016 07.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Structure-function studies on steroid transforming enzymes often use site-directed mutagenesis to inform mechanisms of catalysis and effects on steroid binding, and data are reported in terms of changes in steady state kinetic parameters kcat, Km and kcat/Km. However, this dissection of function is limited since kcat is governed by the rate-determining step and Km is a complex macroscopic kinetic constant. Often site-directed mutagenesis can lead to a change in the rate-determining step which cannot be revealed by just reporting a decrease in kcat alone. These issues are made more complex when it is considered that many steroid transforming enzymes have more than one substrate and product. We present the case for using transient-kinetics performed with stopped-flow spectrometry to assign rate constants to discrete steps in these multi-substrate reactions and their use to interpret enzyme mechanism and the effects of disease and engineered mutations. We demonstrate that fluorescence kinetic transients can be used to measure ligand binding that may be accompanied by isomerization steps, revealing the existence of new enzyme intermediates. We also demonstrate that single-turnover reactions can provide a klim for the chemical step and Ks for steroid-substrate binding and that when coupled with kinetic isotope effect measurements can provide information on transition state intermediates. We also demonstrate how multiple turnover experiments can provide evidence for either "burst-phase" kinetics, which can reveal a slow product release step, or linear-phase kinetics, in which the chemical step can be rate-determining. With these assignments it becomes more straightforward to analyze the effects of mutations. We use examples from the hydroxysteroid dehydrogenases (AKR1Cs) and human steroid 5ß-reductase (AKR1D1) to illustrate the utility of the approach, which are members of the aldo-keto reductase (AKR) superfamily.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/metabolismo
Ensaios Enzimáticos/instrumentação
Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Animais
Desenho de Equipamento
Seres Humanos
Cinética
Análise Espectral/instrumentação
Esteroides/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Steroids); EC 1.- (Oxidoreductases); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 1.3.99.6 (3-oxo-5 beta-steroid delta 4-dehydrogenase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151125
[St] Status:MEDLINE


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[PMID]:26573806
[Au] Autor:Wenners A; Hartmann F; Jochens A; Roemer AM; Alkatout I; Klapper W; van Mackelenbergh M; Mundhenke C; Jonat W; Bauer M
[Ad] Endereço:Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Arnold-Heller-Str. 3, 24105, Kiel, Germany. antonia.wenners@gmx.de.
[Ti] Título:Stromal markers AKR1C1 and AKR1C2 are prognostic factors in primary human breast cancer.
[So] Source:Int J Clin Oncol;21(3):548-56, 2016 Jun.
[Is] ISSN:1437-7772
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo-keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. METHODS: Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. RESULTS: AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. CONCLUSION: It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/análise
Neoplasias da Mama/química
Neoplasias da Mama/patologia
Carcinoma/química
Fibroblastos/química
Hidroxiesteroide Desidrogenases/análise
[Mh] Termos MeSH secundário: Biomarcadores/análise
Carcinoma/secundário
Intervalo Livre de Doença
Feminino
Seres Humanos
Imuno-Histoquímica
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Taxa de Sobrevida
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 1.1.1.357 (AKR1C2 protein, human)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151118
[St] Status:MEDLINE
[do] DOI:10.1007/s10147-015-0924-2


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[PMID]:26388291
[Au] Autor:Kato D; Suzuki Y; Haga S; So K; Yamauchi E; Nakano M; Ishizaki H; Choi K; Katoh K; Roh SG
[Ad] Endereço:Lab of Animal Physiology, Graduate School of Agricultural Science, Tohoku University, Sendai.
[Ti] Título:Utilization of digital differential display to identify differentially expressed genes related to rumen development.
[So] Source:Anim Sci J;87(4):584-90, 2016 Apr.
[Is] ISSN:1740-0929
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:This study aimed to identify the genes associated with the development of the rumen epithelium by screening for candidate genes by digital differential display (DDD) in silico. Using DDD in NCBI's UniGene database, expressed sequence tag (EST)-based gene expression profiles were analyzed in rumen, reticulum, omasum, abomasum and other tissues in cattle. One hundred and ten candidate genes with high expression in the rumen were derived from a library of all tissues. The expression levels of 11 genes in all candidate genes were analyzed in the rumen, reticulum, omasum and abomasum of nine Japanese Black male calves (5-week-old pre-weaning: n = 3; 15-week-old weaned calves: n = 6). Among the 11 genes, only 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), aldo-keto reductase family 1, member C1-like (AKR1C1), and fatty acid binding protein 3 (FABP3) showed significant changes in the levels of gene expression in the rumen between the pre- and post-weaning of calves. These results indicate that DDD analysis in silico can be useful for screening candidate genes related to rumen development, and that the changes in expression levels of three genes in the rumen may have been caused by weaning, aging or both.
[Mh] Termos MeSH primário: Bovinos/crescimento & desenvolvimento
Bovinos/genética
Perfilação da Expressão Gênica/métodos
Expressão Gênica
Estudos de Associação Genética/veterinária
Testes Genéticos/métodos
Rúmen/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: 20-Hidroxiesteroide Desidrogenases/genética
Envelhecimento/genética
Animais
Simulação por Computador
Epitélio/crescimento & desenvolvimento
Etiquetas de Sequências Expressas
Proteína 3 Ligante de Ácido Graxo
Proteínas de Ligação a Ácido Graxo/genética
Hidroximetilglutaril-CoA Sintase/genética
Masculino
Especificidade de Órgãos/genética
Desmame
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (FABP3 protein, human); 0 (Fatty Acid Binding Protein 3); 0 (Fatty Acid-Binding Proteins); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150922
[St] Status:MEDLINE
[do] DOI:10.1111/asj.12448


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[PMID]:26452127
[Au] Autor:Kozlovich S; Chen G; Lazarus P
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University , Spokane, Washington 99202, United States.
[Ti] Título:Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL.
[So] Source:Chem Res Toxicol;28(11):2112-9, 2015 Nov 16.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Among the most potent carcinogens in tobacco are the tobacco-specific nitrosamines (TSNAs), with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the most potent as well as one of the most abundant. NNK is extensively metabolized to the equally carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Of the two NNAL enantiomers, (S)-NNAL not only appears to be preferentially glucuronidated and excreted in humans but also exhibits higher stereoselective tissue retention in mice and humans and has been shown to be more carcinogenic in mice than its (R) counterpart. Due to the differential carcinogenic potential of the NNAL enantiomers, it is increasingly important to know which UGT enzyme targets the specific NNAL enantiomers for glucuronidation. To examine this, a chiral separation method was developed to isolate enantiomerically pure (S)- and (R)-NNAL. Comparison of NNAL glucuronides (NNAL-Glucs) formed in reactions of UGT2B7-, UGT2B17-, UGT1A9-, and UGT2B10-overexpressing cell microsomes with pure NNAL enantiomers showed large differences in kinetics for (S)- versus (R)-NNAL, indicating varying levels of enantiomeric preference for each enzyme. UGT2B17 preferentially formed (R)-NNAL-O-Gluc, and UGT2B7 preferentially formed (S)-NNAL-O-Gluc. When human liver microsomes (HLM) were independently incubated with each NNAL enantiomer, the ratio of (R)-NNAL-O-Gluc to (S)-NNAL-O-Gluc formation in HLM from subjects exhibiting the homozygous deletion UGT2B17 (*2/*2) genotype was significantly lower (p = 0.012) than that with HLM from wild-type (*1/*1) subjects. There was a significant trend (p = 0.015) toward a decreased (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc ratio as the copy number of the UGT2B17*2 deletion allele increased. These data demonstrate that variations in the expression or activity of specific UGTs may affect the clearance of specific NNAL enantiomers known to induce tobacco-related cancers.
[Mh] Termos MeSH primário: Carcinógenos/química
Carcinógenos/metabolismo
Glucuronosiltransferase/metabolismo
Nitrosaminas/química
Nitrosaminas/metabolismo
Piridinas/química
Piridinas/metabolismo
[Mh] Termos MeSH secundário: 20-Hidroxiesteroide Desidrogenases/genética
20-Hidroxiesteroide Desidrogenases/metabolismo
Escherichia coli/genética
Glucuronídeos/metabolismo
Células HEK293
Seres Humanos
Microssomos Hepáticos/metabolismo
Estereoisomerismo
Tabaco
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carcinogens); 0 (Glucuronides); 0 (Nitrosamines); 0 (Pyridines); 7S395EDO61 (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 2.4.1.17 (Glucuronosyltransferase); EN7PIX794W (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151010
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.5b00278


  9 / 398 MEDLINE  
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[PMID]:26362498
[Au] Autor:Zhao Y; Zheng X; Zhang H; Zhai J; Zhang L; Li C; Zeng K; Chen Y; Li Q; Hu X
[Ad] Endereço:School of Pharmaceutical Sciences & Centre for Cellular and Structural Biology of Sun Yat-sen University, Guangzhou 510006, China.
[Ti] Título:In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis.
[So] Source:Chem Biol Interact;240:310-5, 2015 Oct 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Recent epidemiological studies show conflicting data for the first-line anti-diabetic sulphonylureas drugs in treating cancer progression in type II diabetes patients. How sulphonylureas promote or diminish tumor growth is not fully understood. Here, we report that seven sulphonylureas exhibit different in vitro inhibition towards AKR1Cs (AKR1C1, AKR1C2, AKR1C3), which are critical steroid hormone metabolism enzymes that are related to prostate cancer, breast cancer and endometrial diseases. Interactions of the sulphonylureas and AKR1Cs were analyzed by X-ray crystallography.
[Mh] Termos MeSH primário: 20-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores
Hidroxiesteroide Desidrogenases/antagonistas & inibidores
Modelos Moleculares
Compostos de Sulfonilureia/classificação
Compostos de Sulfonilureia/farmacologia
[Mh] Termos MeSH secundário: Membro C3 da Família 1 de alfa-Ceto Redutase
Sítios de Ligação
Seres Humanos
Concentração Inibidora 50
Estrutura Molecular
Compostos de Sulfonilureia/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sulfonylurea Compounds); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C2 protein, human); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150913
[St] Status:MEDLINE


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[PMID]:26338969
[Au] Autor:Liu C; Guo H; Cheng X; Shao M; Wu C; Wang S; Li H; Wei L; Gao Y; Tan W; Cheng S; Wu T; Yu D; Lin D
[Ad] Endereço:State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
[Ti] Título:Exposure to airborne PM2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells.
[So] Source:Oncotarget;6(30):29428-39, 2015 Oct 06.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Long-term exposure to airborne PM2.5 is associated with increased lung cancer risk but the underlying mechanism remains unclear. We characterized global microRNA and mRNA expression in human bronchial epithelial cells exposed to PM2.5 organic extract and integrally analyzed microRNA-mRNA interactions. Foci formation and xenograft tumorigenesis in mice with NIH3T3 cells expressing genes targeted by microRNAs were performed to explore the oncogenic potential of these genes. We also detected plasma levels of candidate microRNAs in subjects exposed to different levels of air PM2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM2.5 extract resulted in downregulation of 138 microRNAs and aberrant expression of 13 mRNAs (11 upregulation and 2 downregulation). In silico and biochemical analyses suggested SLC30A1, SERPINB2 and AKR1C1, among the upregulated genes, as target for miR-182 and miR-185, respectively. Ectopic expression of each of these genes significantly enhanced foci formation in NIH3T3 cells. Following subcutaneous injection of these cells into nude mice, fibrosarcoma were formed from SLC30A1- or SERPINB2-expressing cells. Reduced plasma levels of miR-182 were detected in subjects exposed to high level of PM2.5 than in those exposed to low level of PM2.5 (P = 0.043). Similar results were seen for miR-185 although the difference was not statistically significant (P = 0.328). Increased expressions of SLC30A1, SERPINB2 and AKR1C1 were detected in human lung cancer. These results suggest that modulation of miR-182 and miR-185 and their target genes may contribute to lung carcinogenesis attributable to PM2.5 exposure.
[Mh] Termos MeSH primário: Poluentes Atmosféricos/toxicidade
Biomarcadores Tumorais/metabolismo
Brônquios/efeitos dos fármacos
Transformação Celular Neoplásica/induzido quimicamente
Células Epiteliais/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Neoplasias Pulmonares/induzido quimicamente
MicroRNAs/metabolismo
Oncogenes
Material Particulado/toxicidade
[Mh] Termos MeSH secundário: 20-Hidroxiesteroide Desidrogenases/genética
20-Hidroxiesteroide Desidrogenases/metabolismo
Animais
Biomarcadores Tumorais/genética
Brônquios/metabolismo
Brônquios/patologia
Proteínas de Transporte de Cátions/genética
Proteínas de Transporte de Cátions/metabolismo
Linhagem Celular Tumoral
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Transformação Celular Neoplásica/patologia
Simulação por Computador
Regulação para Baixo
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Fibroblastos/metabolismo
Fibroblastos/patologia
Fibroblastos/transplante
Perfilação da Expressão Gênica/métodos
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Neoplasias Pulmonares/sangue
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
MicroRNAs/sangue
MicroRNAs/genética
Células NIH 3T3
Projetos Piloto
Inibidor 2 de Ativador de Plasminogênio/genética
Inibidor 2 de Ativador de Plasminogênio/metabolismo
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Air Pollutants); 0 (Biomarkers, Tumor); 0 (Cation Transport Proteins); 0 (MicroRNAs); 0 (Mirn182 microRNA, human); 0 (Particulate Matter); 0 (Plasminogen Activator Inhibitor 2); 0 (SLC30A1 protein, human); EC 1.1.1.- (20-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160224
[Lr] Data última revisão:
160224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150905
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.5005



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