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Pesquisa : D08.811.913.050.134.138 [Categoria DeCS]
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[PMID]:29180287
[Au] Autor:Hein DW; Zhang X; Doll MA
[Ad] Endereço:Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY USA. Electronic address: d.hein@louisville.edu.
[Ti] Título:Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation.
[So] Source:Toxicol Lett;283:100-105, 2018 Feb.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the acetylation of arylamine carcinogens. Single nucleotide polymorphisms in the NAT2 coding exon present in NAT2 haplotypes encode allozymes with reduced N-acetyltransferase activity towards the N-acetylation of arylamine carcinogens and the O-acetylation of their N-hydroxylated metabolites. NAT2 acetylator phenotype modifies urinary bladder cancer risk following exposures to arylamine carcinogens such as 4-aminobiphenyl. 4, 4'-methylene bis (2-chloroaniline) (MOCA) is a Group 1 carcinogen for which a role of the NAT2 acetylation polymorphism on cancer risk is unknown. We investigated the role of NAT2 and the genetic acetylation polymorphism on both MOCA N-acetylation and N-hydroxy-MOCA O-acetylation. MOCA N-acetylation exhibited a robust gene dose response in rabbit liver cytosol and in cryopreserved human hepatocytes derived from individuals of rapid, intermediate and slow acetylator NAT2 genotype. MOCA exhibited about 4-fold higher affinity for recombinant human NAT2 than NAT1. Recombinant human NAT2*4 (reference) and 15 variant recombinant human NAT2 allozymes catalyzed both the N-acetylation of MOCA and the O-acetylation of N-hydroxy-MOCA. Human NAT2 5, NAT2 6, NAT2 7 and NAT2 14 allozymes catalyzed MOCA N-acetylation and N-hydroxy-O-acetylation at rates much lower than the reference NAT2 4 allozyme. In conclusion, our results show that NAT2 acetylator genotype has an important role in MOCA metabolism and suggest that risk assessments related to MOCA exposures consider accounting for NAT2 acetylator phenotype in the analysis.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/genética
Arilamina N-Acetiltransferase/metabolismo
Carcinógenos/metabolismo
Metilenobis (cloroanilina)/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Animais
Biotransformação
Citosol/metabolismo
Hepatócitos/enzimologia
Hepatócitos/metabolismo
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Polimorfismo Genético
Coelhos
Proteínas Recombinantes
Neoplasias da Bexiga Urinária/induzido quimicamente
Neoplasias da Bexiga Urinária/genética
Neoplasias da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carcinogens); 0 (Isoenzymes); 0 (Recombinant Proteins); 3L2W5VTT2A (Methylenebis(chloroaniline)); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE


  2 / 2709 MEDLINE  
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[PMID]:29049179
[Au] Autor:Zou Y; Dong S; Xu S; Gong Q; Chen J
[Ad] Endereço:Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
[Ti] Título:Genetic polymorphisms of NAT2 and risk of acute myeloid leukemia: A case-control study.
[So] Source:Medicine (Baltimore);96(42):e7499, 2017 Oct.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our purpose was to investigate the possible associations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of acute myeloid leukemia (AML) in Chinese Han population.A case-control study was conducted including 98 AML cases and 112 healthy controls. NAT2 gene 2 polymorphisms rs1799930 and rs1799931 were genotyped using direct sequencing. Chi-square test was performed to compare the genotype and allele distribution differences between groups. Odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between NAT2 gene polymorphisms and AML onset.A remarkable decrease trend of rs1799931 GA genotype was detected in AML patients compared with controls, whereas the ancestral GG genotype frequency increased in cases (P < .05). And the mutant A allele of rs1799931 significantly reduced the risk of AML by 0.585-fold versus the ancestral G allele carriers (OR = 0.585, 95% CI = 0.361-0.950). But the distributions of rs1799930 genotype and allele were similar between groups (P > .05).Our findings suggested that NAT2 gene polymorphism rs1799931 was associated with decreased risk of AML and was likely to be a protective factor against AML development.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/genética
Grupo com Ancestrais do Continente Asiático/genética
Predisposição Genética para Doença/genética
Leucemia Mieloide Aguda/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Alelos
Arilamina N-Acetiltransferase/sangue
Estudos de Casos e Controles
Distribuição de Qui-Quadrado
China/etnologia
Feminino
Genótipo
Seres Humanos
Masculino
Meia-Idade
Razão de Chances
Fatores de Risco
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171020
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007499


  3 / 2709 MEDLINE  
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[PMID]:29036176
[Au] Autor:Chan SL; Chua APG; Aminkeng F; Chee CBE; Jin S; Loh M; Gan SH; Wang YT; Brunham LR
[Ad] Endereço:Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore.
[Ti] Título:Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients.
[So] Source:PLoS One;12(10):e0186200, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population. METHODS: This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants. RESULTS: Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30-44.70), 0.10 (0.03-0.33) and 9.98 (3.32-33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027). CONCLUSIONS: We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.
[Mh] Termos MeSH primário: Antituberculosos/toxicidade
Arilamina N-Acetiltransferase/genética
Doença Hepática Induzida por Substâncias e Drogas/genética
Isoniazida/toxicidade
[Mh] Termos MeSH secundário: Antituberculosos/uso terapêutico
Biomarcadores Farmacológicos
Estudos de Casos e Controles
Feminino
Predisposição Genética para Doença
Seres Humanos
Isoniazida/uso terapêutico
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único
Prognóstico
Singapura
Tuberculose/complicações
Tuberculose/tratamento farmacológico
Tuberculose/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Biomarkers, Pharmacological); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); V83O1VOZ8L (Isoniazid)
[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:171017
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186200


  4 / 2709 MEDLINE  
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[PMID]:28906376
[Au] Autor:Yan J; Song H; Mi N; Jiao X; Hao Y
[Ad] Endereço:aDepartment of Stomatology, Harbin Medical University Cancer Hospital bDepartment of Oral Maxillofacial Surgery, the First Affiliated Hospital cDepartment of Endodontics, the First Affiliated Hospital, Harbin Medical University, Harbin dDepartment of Stomatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China.
[Ti] Título:Nucleotide variants of the NAT2 and EGF61 genes in patients in Northern China with nonsyndromic cleft lip with or without cleft palate.
[So] Source:Medicine (Baltimore);96(37):e7973, 2017 Sep.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common orofacial congenital anomaly. The objective of the present study was to analyze the association of single nucleotide polymorphisms (SNPs) in the NAT2 and EGF61genes with NSCL/P in a Chinese population. METHODS: The frequencies of NAT2 (rs1799929)and EGF61 (rs4444903) gene variations were examined in a group of 285 NSCL/P patients and in 315 controls. Peripheral venous blood samples were collected for DNA extraction. Genotyping of the 2 SNPs was carried out using a mini sequencing (SNaPshot) method. Data were analyzed using the chi-square test. RESULTS: We found a significant association between the EGF61 (rs4444903) and NSCL/P (P = .01) genes.Conversely, NAT2 (rs1799929) was not significantly different between the cases and the control group.The genotype frequencies of rs4444903GA showed a significant difference compared with GG genotype as a reference (odds ratio = 0.59; 95% confidence interval: 0.42-0.84, P = .01). CONCLUSION: Our study showed that the EGF61 rs4444903GA genotype had a decreased risk of NSCL/P. Our data provides further evidence regarding the role of EGF61 variations in the development of NSCL/P in families of the studied populations.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/genética
Fenda Labial/genética
Fissura Palatina/genética
Fator de Crescimento Epidérmico/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático/genética
Genótipo
Seres Humanos
Nucleotídeos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides); 62229-50-9 (Epidermal Growth Factor); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007973


  5 / 2709 MEDLINE  
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[PMID]:28817838
[Au] Autor:Lévi F; Karaboué A; Saffroy R; Desterke C; Boige V; Smith D; Hebbar M; Innominato P; Taieb J; Carvalho C; Guimbaud R; Focan C; Bouchahda M; Adam R; Ducreux M; Milano G; Lemoine A
[Ad] Endereço:INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.
[Ti] Título:Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).
[So] Source:Br J Cancer;117(7):965-973, 2017 Sep 26.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Arilamina N-Acetiltransferase/genética
Neoplasias Colorretais/genética
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/genética
Vitamina K Epóxido Redutases/genética
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Administração Intravenosa
Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Camptotecina/administração & dosagem
Camptotecina/análogos & derivados
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Cetuximab/administração & dosagem
Neoplasias Colorretais/patologia
Citocromo P-450 CYP2C19/genética
Citocromo P-450 CYP2C9/genética
Diarreia/induzido quimicamente
Diarreia/genética
Intervalo Livre de Doença
Feminino
Fluoruracila/administração & dosagem
Glucuronosiltransferase/genética
Hepatectomia
Artéria Hepática
Seres Humanos
Infusões Intra-Arteriais
Neoplasias Hepáticas/secundário
Neoplasias Hepáticas/cirurgia
Masculino
Meia-Idade
Neutropenia/induzido quimicamente
Neutropenia/genética
Compostos Organoplatínicos/administração & dosagem
Farmacogenética
Polimorfismo de Nucleotídeo Único
Taxa de Sobrevida
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organoplatinum Compounds); 0 (Slc22a1 protein, mouse); 04ZR38536J (oxaliplatin); 7673326042 (irinotecan); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.17.4.4 (VKORC1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A6); EC 2.4.1.17 (Glucuronosyltransferase); PQX0D8J21J (Cetuximab); U3P01618RT (Fluorouracil); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.278


  6 / 2709 MEDLINE  
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[PMID]:28696911
[Au] Autor:Höhne S; Gerullis H; Blaszkewicz M; Selinski S; Hengstler JG; Otto T; Golka K
[Ad] Endereço:a Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo) , Dortmund , Germany.
[Ti] Título:N-acetyltransferase 1*10 genotype in bladder cancer patients.
[So] Source:J Toxicol Environ Health A;80(7-8):417-422, 2017.
[Is] ISSN:1528-7394
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In a large bladder cancer study in the greater Berlin area with 425 cases and 343 controls, the haplotype N-acetyltransferase 1*10 (NAT1*10) was associated with a decreased bladder cancer risk. In a recently published meta-analysis, results of the studies were found to be inconclusive. Therefore, the aim of this study was to investigate the frequency of NAT1*10 in bladder cancer patients and controls recruited in an area without industries reported to be associated with increased bladder cancer risk. Rs1057126 (1088 T > A) and rs15561 (1095 C > A) were determined in 412 bladder cancer patients and 415 controls without a known history of malignancies. With these two single-nucleotide polymorphisms (SNP), it was possible to distinguish between NAT1*4 (wild type), NAT1*3 (1095 C > A), and NAT1*10 (1088 T > A, 1095C > A). The frequencies of the determined NAT1 haplotypes did not differ markedly between cases and controls: NAT1*4: 74%, NAT1*3: 6%, NAT1*10: 20%. Bladder cancer risk was not significantly modulated by NAT1*10/*10 (OR 1.03, 95% CI 0.71-1.48) but was higher for NAT1*3/*3 genotypes (OR 2.05, 95% CI 1.32-3.21). In contrast to the Berlin study from 2001, data in present study demonstrated that NAT1*10 haplotype was not associated with a significantly decreased bladder cancer risk. This may be due to local effects in the greater Berlin area, particularly at the time of investigation. The findings of the present study are in agreement with observations of a recently published meta-analysis which also showed no relevant impact of NAT1*10 haplotype on bladder cancer risk. The impact of the rare NAT1*3/*3 genotype was significant but this may be attributed to rarity without major practical relevance.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/genética
Isoenzimas/genética
Polimorfismo de Nucleotídeo Único
Neoplasias da Bexiga Urinária/genética
[Mh] Termos MeSH secundário: Berlim
Haplótipos
Seres Humanos
Razão de Chances
Neoplasias da Bexiga Urinária/enzimologia
Neoplasias da Bexiga Urinária/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (N-acetyltransferase 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1080/10937404.2017.1304727


  7 / 2709 MEDLINE  
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[PMID]:28696897
[Au] Autor:Ebbinghaus D; Bánfi G; Selinski S; Blaszkewicz M; Bürger H; Hengstler JG; Nyirády P; Golka K
[Ad] Endereço:a Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo) , Dortmund, Germany.
[Ti] Título:Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary.
[So] Source:J Toxicol Environ Health A;80(7-8):423-429, 2017.
[Is] ISSN:1528-7394
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/genética
Genótipo
Glutationa Transferase/genética
Polimorfismo Genético
Neoplasias da Bexiga Urinária/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Feminino
Seres Humanos
Hungria
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 2.5.1.- (glutathione S-transferase T1); EC 2.5.1.18 (Glutathione Transferase); EC 2.5.1.18 (glutathione S-transferase M1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1080/10937404.2017.1304736


  8 / 2709 MEDLINE  
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[PMID]:28674152
[Au] Autor:Xu X; Mathieu C; Berthelet J; Duval R; Bui LC; Busi F; Dupret JM; Rodrigues-Lima F
[Ad] Endereço:Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, Paris, France (X.X., C.M., J.B., R.D., L.C.B., F.B., J.-M.D., F.R.L.); and Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, Chin
[Ti] Título:Human Arylamine -Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram.
[So] Source:Mol Pharmacol;92(3):358-365, 2017 Sep.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thiram (tetramethylthiuram disulfide) is a representative dithiocarbamate (DTC) pesticide used in both the field and as a seed protectant. The widespread use of Thiram and other DTC pesticides has raised concerns for health, because these compounds can exert neuropathic, endocrine disruptive, and carcinogenic effects. These toxic effects are thought to rely, at least in part, on the reaction of Thiram (and certain of its metabolites) with cellular protein thiols with subsequent loss of protein function. So far, a limited number of molecular targets of Thiram have been reported, including few enzymes such as dopamine -hydroxylase, 11 -hydroxysteroid dehydrogenase, and brain glycogen phosphorylase. We provide evidence that Thiram is an inhibitor ( = 23 M; = 0.085 second ; / = 3691 M â‹…s ) of human arylamine -acetyltransferase 1 (NAT1), a phase II xenobiotic-metabolizing enzyme that plays a key role in the biotransformation of aromatic amine xenobiotics. Thiram was found to act as an irreversible inhibitor through the modification of NAT1 catalytic cysteine residue as also reported for other enzymes targeted by this pesticide. We also showed using purified NAT1 and human keratinocytes that Thiram impaired the -acetylation of 3,4-dichloroaniline (3,4-DCA), a major toxic metabolite of aromatic amine pesticides (such as Diuron or Propanil). As coexposure to different classes of pesticides is common, our data suggest that pharmacokinetic drug-drug interactions between DTC pesticides such as Thiram and aromatic amine pesticides may occur through alteration of NAT1 enzymes functions.
[Mh] Termos MeSH primário: Arilamina N-Acetiltransferase/antagonistas & inibidores
Fungicidas Industriais/farmacologia
Isoenzimas/antagonistas & inibidores
Tiram/farmacologia
[Mh] Termos MeSH secundário: Acetilação
Compostos de Anilina/metabolismo
Células Cultivadas
Ditiotreitol/farmacologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Fungicides, Industrial); 0 (Isoenzymes); 0D771IS0FH (Thiram); 20KR9WJ4NS (3,4-dichloroaniline); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (N-acetyltransferase 1); T8ID5YZU6Y (Dithiothreitol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE
[do] DOI:10.1124/mol.117.108662


  9 / 2709 MEDLINE  
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[PMID]:28606603
[Au] Autor:Konishi K; Fukami T; Gotoh S; Nakajima M
[Ad] Endereço:Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
[Ti] Título:Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.
[So] Source:Biochem Pharmacol;140:150-160, 2017 Sep 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N -methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-l-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.
[Mh] Termos MeSH primário: Aldeído Oxidase/metabolismo
Arilamina N-Acetiltransferase/metabolismo
Hidrolases de Éster Carboxílico/metabolismo
Citocromo P-450 CYP3A/metabolismo
Hepatócitos/metabolismo
Hipnóticos e Sedativos/metabolismo
Nitrazepam/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Aldeído Oxidase/antagonistas & inibidores
Aldeído Oxidase/química
Aldeído Oxidase/isolamento & purificação
Arilamina N-Acetiltransferase/genética
Biotransformação
Hidrolases de Éster Carboxílico/genética
Citocromo P-450 CYP3A/genética
Citosol/enzimologia
Citosol/metabolismo
Inibidores Enzimáticos/farmacologia
Hepatócitos/enzimologia
Seres Humanos
Hidrólise/efeitos dos fármacos
Hidroxilação
Hipnóticos e Sedativos/efeitos adversos
Cinética
Microssomos Hepáticos/enzimologia
Microssomos Hepáticos/metabolismo
Nitrazepam/efeitos adversos
Nitrazepam/análogos & derivados
Oxirredução
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Hypnotics and Sedatives); 0 (Recombinant Proteins); 1A49O337AZ (7-aminonitrazepam); 4928-03-4 (7-acetamidonitrazepam); 9CLV70W7HS (Nitrazepam); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.2.3.1 (AOX1 protein, human); EC 1.2.3.1 (Aldehyde Oxidase); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 3.1.1.- (AADAC protein, human); EC 3.1.1.- (Carboxylic Ester Hydrolases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE


  10 / 2709 MEDLINE  
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[PMID]:28560658
[Au] Autor:Ding Y; Zhang H; Li X; Li C; Chen G; Chen H; Wu M; Niu J
[Ad] Endereço:Phase I Clinical Trial Unit, The First Hospital of Jilin University, Changchun, No. 71 Xinmin Street, Changchun, 130021, China.
[Ti] Título:Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects.
[So] Source:Hepatol Int;11(4):390-400, 2017 Jul.
[Is] ISSN:1936-0541
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. METHODS: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. RESULTS: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C ) and area under the curve (AUC) of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C and AUC of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. CONCLUSIONS: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. TRIAL REGISTRATION NUMBER: CTR20140341.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Arilamina N-Acetiltransferase/genética
Sistema Enzimático do Citocromo P-450/genética
Família 2 do Citocromo P450/genética
Isoenzimas/genética
Compostos Organofosforados/administração & dosagem
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adenina/administração & dosagem
Adenina/efeitos adversos
Adenina/farmacocinética
Adulto
Esquema de Medicação
Feminino
Voluntários Saudáveis
Seres Humanos
Masculino
Compostos Organofosforados/efeitos adversos
Compostos Organofosforados/farmacocinética
Variantes Farmacogenômicos
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Organophosphorus Compounds); 0 (POR protein, human); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (CYP2F1 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (N-acetyltransferase 1); GZE85Q9Q61 (pradefovir); JAC85A2161 (Adenine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1007/s12072-017-9797-y



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