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Polimorfismos nos genes NAT2, CYP2E1, GSTT1, GSTM1 e ABCB11 e hepatotoxicidade induzida pela isoniazida

Carvalho, Maria Teresa Penetra Moura de
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
ENG
Relevância na Pesquisa
27.71%
A isoniazida (INH) é essencial ao tratamento da tuberculose mas é, igualmente, um dos fármacos mais frequentemente associados a episódios de hepatotoxicidade (HT) graves, por vezes fatais. A suscetibilidade individual a este efeito secundário é um fenótipo multifatorial na dependência de fatores genéticos e não genéticos. A identificação dos fatores genéticos envolvidos pode contribuir para a individualização e otimização da terapêutica. A variabilidade individual dos níveis séricos da INH é determinada essencialmente por polimorfismos da N-acetiltransferase, codificada pelo gene NAT2. A genotipagem do NAT2 permite a identificação dos vários haplótipos, possibilitando a classificação dos indivíduos em acetiladores lentos (AL), de elevado risco para HT, acetiladores intermédios (AI) e rápidos (AR). Outras enzimas polimórficas intervenientes são o citocromo P-450 2E1 (CYP2E1), que converte a INH em metabolitos tóxicos, e as glutationas S-transferases (GST), que para além de contribuírem para o metabolismo da INH também estão envolvidas a resposta do hepatócito à agressão. Assim, a homozigotia para os alelos wild-type, de elevada atividade funcional para o gene CYP2E1 (CYP2E1 *1A/*1A), e variantes genéticas com perda de função correspondentes a delecção em homozigotia para os genes GSTT1 e GSTM1 poderão constituir genótipos de risco. Fatores genéticos que afetem os sistemas de transporte biliar...

Análise dos polimorfismos GSTM1 e GSTT1 em pacientes que desenvolveram leucemias agudas

Rohr, Paula; Delgado-Cañedo, Andrés; Paskulin, Giorgio Adriano; Schüller, Ivan; Nardi, Nance Beyer; Kvitko, Katia
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Artigo de Revista Científica Formato: application/pdf
POR
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(Análise dos polimorfismos GSTM1 e GSTT1 em pacientes que desenvolveram leucemias agudas) – A leucemia é uma neoplasia que acomete a medula óssea. No caso das Leucemias Agudas (LA), as células em proliferação são imaturas ou blastos. A etiologia das LA pode ser explicada pela combinação de fatores genéticos e ambientais. Como exemplo das influências genéticas pode-se citar polimorfismos de genes de metabolização/detoxificação. Este trabalho tem por objetivo analisar os polimorfismos dos genes GSTM1 e GSTT1 em relação à suscetibilidade de desenvolvimento de LA. O DNA genômico de 87 pacientes (24 mielóides, 35 linfóides e 28 sem classificação determinada) foi analisado pela técnica de PCR multiplex. A idade dos pacientes variou entre seis meses e 80 anos, sendo 35 femininos e 52 masculinos. Foi detectado aumento significativo da freqüência do genótipo GSTT1 nulo quando comparado com uma população controle (41,37% X 23%) (P=0.005). A freqüência do genótipo nulo para GSTM1 nos pacientes não apresentou diferença significativa com relação aos controles (49,42% X 50%). Com isso, sugerimos que o gene GSTT1 parece estar envolvido na suscetibilidade para o desenvolvimento de LA.; (Polymorphism analyses of GSTM1 and GSTT1 genes in Acute Leukemia patients) – Leukemia is a neoplasic disease that affects bone-marrow cells. In case of Acute Leukemia (AL) the proliferating cells are immature or blasts. The causes of AL are likely to involve an interaction between genetic susceptibility and environment. Polymorphisms in genes coding metabolizing/ detoxification enzymes are responsible for this susceptibility. The aim of this study was to analyze polymorphisms of GSTM1 and GSTT1 genes in order to verify if they have a role in genetic susceptibility to AL. Genomic DNA from 87 patients (24 myeloblastic...

GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submetted to breast cancer screening; Polimorfismos GSTM1, GSTT1 e GSTP1, fatores de risco para câncer de mama e densidade mamográfica em mulheres submetidas a rastreamento mamográfico

Aguiar, Ernestina Silva de; Giacomazzi, Juliana; Schmidt, Aishameriane Venes; Bock, Hugo; Pereira, Maria Luiza Saraiva; Faccini, Lavinia Schuler; Duarte Filho, Dakir Lourenço; Santos, Pollyanna Almeida Costa dos; Giugliani, Roberto; Caleffi, Maira; Camey
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
Relevância na Pesquisa
37.76%
Polimorfismos genéticos em genes relacionados com o metabolismo de xenobióticos, como os genes da superfamília das glutationa S-transferases (GSTM1, GSTT1 e GSTP1) têm sido associados com o aumento do risco para câncer de mama (CM). Considerando a alta incidência de CM na cidade de Porto Alegre, região Sul do Brasil, a proposta deste estudo foi caracterizar genótipos e frequências alélicas dos polimorfismos GSTM1, GSTT1 e GSTP1, e correlacionar esses achados moleculares com fatores de risco já estabelecidos para câncer de mama, incluindo densidade mamográfica, em uma amostra de 750 mulheres assintomáticas durante o rastreamento mamográfico. Para os testes moleculares foi utilizado multiplex da reação em cadeia de polimerase (PCR) para GSTM1 e GSTT1, e PCR quantitativo para o polimorfismo GSTP1. As frequências dos genótipos GSTM1 e GSTT1 nulos foram 45% e 21%, respectivamente. Para o polimorfismo GSTP1, as frequências genotipicas foram: 44% para o genótipo Ile/Ile, 44% para o genótipo Ile/Val e 12% para o genótipo Val/Val. A frequência do alelo lle nesta população foi 66%, semelhante a outros estudos. Houve uma associação significativa entre a combinação dos genótipos (T-/M-) nulos e densidade mamográfica nas mulheres pós-menopáusicas (p = 0...

Polimorfismos dos genes GSTM1 e GSTT1, do sistema da Glutationa S-Transferase, e T6235C e A4889G do gene CYP1A1, do sistema do Citocromo P450, na susceptibilidade ao carcinoma de celulas escamosas de cabeça e pescoço; GSTM1 eandGSTT1 genes polymorphisms of Glutathione S-Transferase system, and T6235C and A4889G of CYP1A1 gene, by Cytochrome P450 system, in head and neck squamous cell carcinoma susceptibility

Erica Furquim Soledade Neves Silva
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 22/11/2007 PT
Relevância na Pesquisa
27.77%
As glutationa S-transferases (GSTs) são enzimas detoxificantes que atuam no mecanismo de proteção contra a carcinogênese. Os genes GSTM1 e o GSTT1 são polimórficos em humanos e estão deletados de forma homozigótica em 40-50% e 15-25% dos indivíduos de diferentes populações étnicas, respectivamente. Os polimorfismos T6235C e A4889G do gene CYP1A1 estão também associados ao metabolismo de carcinógenos e as formas variantes CC e GG são identificadas em 5-20% e 5% dos indivíduos de diferentes populações étnicas. O objetivo deste estudo é avaliar se os polimorfismos destes genes influenciam o risco de ocorrência do carcinoma epidermóide (CEC) de cabeça e pescoço ou se estão associados com os aspectos clínicos dos pacientes com a doença. Para tanto, foram avaliados 142 pacientes com CEC de cabeça e pescoço e 142 controles. A genotipagem foi realizada por meio da reação em cadeia da polimerase (multiplex-PCR) e PCR e digestão enzimática, respectivamente. O significado estatístico das diferenças entre grupos foi calculado por meio do teste da probabilidade exata de Fisher. As determinações dos riscos de ocorrência do CEC, foram obtidas por meio das razões das chances (ORs) considerando um intervalo de confiança de 95% (IC 95%). Não foram observadas diferenças entre as freqüências da deleção homozigótica dos genes GSTM1 (40...

Ethnicity and glutathione S-transferase (GSTM1/GSTT1) polymorphisms in a Brazilian population

Gattás,G.J.F.; Kato,M.; Soares-Vieira,J.A.; Siraque,M.S.; Kohler,P.; Gomes,L.; Rego,M.A.V.; Bydlowski,S.P.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2004 EN
Relevância na Pesquisa
37.43%
The distribution of polymorphisms related to glutathione S-transferases (GST) has been described in different populations, mainly for white individuals. We evaluated the distribution of GST mu (GSTM1) and theta (GSTT1) genotypes in 594 individuals, by multiplex PCR-based methods, using amplification of the exon 7 of CYP1A1 gene as an internal control. In São Paulo, 233 whites, 87 mulattos, and 137 blacks, all healthy blood-donor volunteers, were tested. In Bahia, where black and mulatto populations are more numerous, 137 subjects were evaluated. The frequency of the GSTM1 null genotype was significantly higher among whites (55.4%) than among mulattos (41.4%; P = 0.03) and blacks (32.8%; P < 0.0001) from São Paulo, or Bahian subjects in general (35.7%; P = 0.0003). There was no statistically different distribution among any non-white groups. The distribution of GSTT1 null genotype among groups did not differ significantly. The agreement between self-reported and interviewer classification of skin color in the Bahian group was low. The interviewer classification indicated a gradient of distribution of the GSTM1 null genotype from whites (55.6%) to light mulattos (40.4%), dark mulattos (32.0%) and blacks (28.6%). However, any information about race or ethnicity should be considered with caution regarding the bias introduced by different data collection techniques...

Características mamográficas do câncer de mama associadas aos polimorfismos GSTM1 e GSTT1

Morais,Lívia Martins Tavares Scianni; Cardoso Filho,Cássio; Lourenço,Gustavo Jacob; Shinzato,Julia Yoriko; Zeferino,Luiz Carlos; Lima,Carmen Sílvia Passos; Gurgel,Maria Salete Costa
Fonte: Associação Médica Brasileira Publicador: Associação Médica Brasileira
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2008 PT
Relevância na Pesquisa
37.57%
INTRODUÇÃO: As enzimas do sistema da glutationa S-transferase (GST) modulam os efeitos da exposição a vários agentes citotóxicos e genotóxicos. Os genes GSTM1 e GSTT1 são polimórficos em humanos e suas deleções têm sido associadas ao aumento do risco de várias neoplasias, dentre elas o câncer de mama. OBJETIVO: Comparar a freqüência das deleções dos genes GSTM1 e GSTT1 em mulheres sadias e com câncer de mama e comparar as características mamográficas do câncer entre mulheres portadoras e não portadoras das referidas deleções. MÉTODOS: Foram determinadas as freqüências das referidas deleções por PCR em 100 pacientes portadoras de câncer de mama esporádico tratadas de setembro de 2004 a junho de 2005 e em 169 mulheres sadias doadoras de sangue no mesmo período e comparadas através do odds ratio (OR) com seus respectivos IC 95%. Foram revistos os prontuários e as mamografias das pacientes com câncer e avaliadas características mamográficas (padrão de distribuição do parênquima fibro-glandular, achados mamográficos ao diagnóstico e classificação BI-RADS), correlacionando-as às deleções gênicas através do cálculo da RP (razão de prevalência) com seus respectivos IC 95%. RESULTADOS: O GSTM1 esteve deletado em 40% dos cânceres e em 44...

Glutathione S-transferase Mu (GSTM1) null genotype in relation to gender, age and smoking status in a healthy Brazilian population

Losi-Guembarovski,Roberta; D’Arce,Luciana Paula Grégio; Cólus,Ilce Mara de Syllos
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2002 EN
Relevância na Pesquisa
37.51%
The glutathione S-transferase mu (GSTM1) gene which acts during phase II of xenobiotic metabolism is polymorphic in the population, being absent in about 30-50% of individuals depending on the ethnic group from which they come. Epidemiological studies suggest that individuals who are homozygous null at the GSTM1 locus may have an increased risk of developing various types of neoplastic disease. We used the polymerase chain reaction (PCR) to estimate the frequency of GSTM1 in 176 healthy individuals from the north of Paraná (Brazilian state), the null genotype being detected in 48.86% of these individuals. The Student’s t-test was used to evaluate the frequency of the glutathione S-transferase null genotype in relation to age, gender and smoking habit and no significant differences were found. In our sample there were 142 individuals of Caucasian origin, of which 47.88% had the null genotype. When applied to the Caucasian group only (n = 142) the Student’s t-test again showed no significant differences between the frequency of the GSTM1 null genotype and age, gender and smoking habit.

No contribution of GSTM1 and GSTT1 null genotypes to the risk of neutropenia due to benzene exposure in Southeastern Brazil

Lima,Carmen Silvia Passos; Lourenço,Gustavo Jacob; Lorand-Metze,Irene; Nascimento,Helvia; Saad,Sara Teresinha Ollala; Costa,Fernando Ferreira
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2009 EN
Relevância na Pesquisa
37.66%
Exposure to benzene has been associated with haematological diseases such as neutropenia (NEB) and acute myeloid leukaemia (AML). We tested whether the null genotypes of the GSTM1 and GSTT1 genes, involved in benzene inactivation, altered the risk for NEB in southeastern Brazil. Genomic DNA from 55 NEB patients and 330 controls was analysed by multiplex-polymerase chain reaction. The frequency of the GSTM1, GSTT1 and combined null genotypes was similar in patients and controls (GSTM1, 27.3% vs. 38.8%, p = 0.16; GSTT1, 25.5% vs. 19.7%, p = 0.24; GSTM1/GSTT1, 12.7% vs. 6.7%, p = 0.26; respectively). The distribution of genotype classes in NEB patients was similar to normal controls, suggesting that GSTM1 and GSTT1 null genotypes make no specific contribution to the risk of NEB. As the GSTM1 and GSTT1 null genotypes were previously associated with increased risk for AML in Brazil and elsewhere, we hypothesise that different thresholds of chemical exposure relative to distinct GSTM1 and GSTT1 genotypes may determine whether AML or NEB manifests in benzene exposed individuals from southeastern Brazil. Although indicative, our results still require support by prospective and large scale epidemiological studies, with rigorous assessment of daily chemical exposures and control of the possible contribution of other polymorphic genes involved in benzene metabolism.

Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genetic polymorphisms and atopic asthma in children from Southeastern Brazil

Lima,Carmen Silvia Passos; Néri,Iramaia Angélica; Lourenço,Gustavo Jacob; Faria,Isabel Cristina Jacinto; Ribeiro,José Dirceu; Bertuzzo,Carmen Silvia
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2010 EN
Relevância na Pesquisa
37.62%
Xenobiotics can trigger degranulation of eosinophils and mast cells. In this process, the cells release several substances leading to bronchial hyperactivity, the main feature of atopic asthma (AA). GSTM1 and GSTT1 genes encode enzymes involved in the inactivation of these compounds. Both genes are polymorphic in humans and have a null variant genotype in which both the gene and corresponding enzyme are absent. An increased risk for disease in individuals with the null GST genotypes is therefore, but this issue is controversial. The aim of this study was to investigate the influence of the GSTM1 and GSTT1 genotypes on the occurrence of AA, as well as on its clinical manifestations. Genomic DNA from 86 patients and 258 controls was analyzed by polymerase chain reaction. The frequency of the GSTM1 null genotype in patients was higher than that found in controls (60.5% versus 40.3%, p = 0.002). In individuals with the GSTM1 null genotype the risk of manifested AA was 2.3-fold higher (95%CI: 1.4-3.7) than for others. In contrast, similar frequencies of GSTT1 null and combined GSTM1 plus GSTT1 null genotypes were seen in both groups. No differences in genotype frequencies were perceived in patients stratified by age, gender, ethnic origin...

Protection against laryngeal and pharyngeal carcinoma: Heterozygous vs. homozygous deletions of GSTM1 and GSTT1

Masood,Nosheen; Kayani,Mahmood Akhtar
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2013 EN
Relevância na Pesquisa
37.57%
Deletions in GSTM1 and GSTT1 genes are considered to be a risk factor for cancer development but the exact location of these deletions in the genome was unknown. Three main objectives of the current study were to: (a) identify the boundaries of these deletions in the human genome, (b) screen homozygous (-/-) and heterozygous (+/-) deleted, as well as homozygous present (+/+) individuals using PCR assays, (c) detect associations of pharyngeal (PC) and laryngeal cancer (LC) with the respective genotypes. In total, 102 PC and 92 LC patients were screened and compared with 150 controls. PCR mapping and sequencing revealed a 6 kbp deletion for GSTM1 and a 9 kbp deletion for the GSTT1 gene. The mean age of PC cases was 48.1 (±16.7) years; for LC cases it was 48.5 (±17.4) years and for controls 46 (±17.7) years. The OR (odds ratio) for the GSTM1 null genotype in PC and LC cases was 10.2 and 1.0 (95% CI 5.04-20.7 and 1.1-1.7) respectively. Similarly, for GSTT1 the OR was 4.02 with a 95% CI of 2.3-7.1 in PC cases. For LC cases the OR was 0.8 with 95% CI of 0.4-1.7. A non-significant number of LC and PC patients had heterozygous deletions of GSTM1 compared to controls (OD 0.5, 95% CI 0.2- 1.6 and OR 0.5, 95% CI 0.2- 1.5 respectively). The GSTT1 gene also showed a non-significant association in PC (OD 0.9...

GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submitted to breast cancer screening

Aguiar,Ernestina Silva de; Giacomazzi,Juliana; Schmidt,Aishameriane Venes; Bock,Hugo; Saraiva-Pereira,Maria Luiza; Schuler-Faccini,Lavínia; Duarte Filho,Dakir; Santos,Pollyanna Almeida Costa dos; Giugliani,Roberto; Caleffi,Maira; Camey,Suzi Alves; Ashton
Fonte: Associação Brasileira de Saúde Coletiva Publicador: Associação Brasileira de Saúde Coletiva
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2012 EN
Relevância na Pesquisa
37.62%
Genetic polymorphisms in genes related to the metabolism of xenobiotics, such as genes of the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) superfamily have been associated with an increased risk for breast cancer (BC). Considering the high incidence of BC in the city of Porto Alegre in southern Brazil, the purpose of this study was to characterize genotypic and allelic frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1, and correlate these molecular findings with established risk factors for breast cancer including mammographic density, in a sample of 750 asymptomatic women undergoing mammographic screening. Molecular tests were performed using the multiplex polymerase chain reaction (PCR) for GSTM1 and GSTT1, and quantitative PCR for GSTP1 polymorphisms. Overall, the frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively. For GSTP1 polymorphism, genotypic frequencies were 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for Val/Val genotype, with an allelic frequency of 66% for the wild type allele in this population, similar to results of previous international publications. There was a statistically significant association between the combined GSTM1 and GSTT1 null genotypes (M-/T-) and mammographic density in post menopausal women (p = 0.031). When the GSTT1 null (T-) genotype was analyzed isolated...

Use of site-directed mutagenesis of allele-specific PCR primers to identify the GSTM1 A, GSTM1 B, GSTM1 A,B and GSTM1 null polymorphisms at the glutathione S-transferase, GSTM1 locus.

Fryer, A A; Zhao, L; Alldersea, J; Pearson, W R; Strange, R C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/10/1993 EN
Relevância na Pesquisa
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We describe the identification of the GSTM1 null, GSTM1 A, GSTM1 B and GSTM1 A,B polymorphisms at the glutathione S-transferase GSTM1 locus using a single-step PCR method. Target DNA was amplified using primers to intron 6 and exon 7 with site-directed mutagenesis being used to introduce a restriction site in DNA amplified from GSTM1 *A, thereby allowing differentiation of this allele and GSTM1 *B. The accuracy of this approach in identifying the GSTM1 A, GSTM1 B, GSTM1 A,B and GSTM1 null polymorphisms was confirmed by comparison with, firstly, an established PCR method that distinguishes GSTM1 *0 homozygotes from individuals with the other GSTM1 genotypes and, secondly, GSTM1 phenotypes determined using chromatofocusing.

GSTM1 null polymorphism at the glutathione S-transferase M1 locus: phenotype and genotype studies in patients with primary biliary cirrhosis.

Davies, M H; Elias, E; Acharya, S; Cotton, W; Faulder, G C; Fryer, A A; Strange, R C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1993 EN
Relevância na Pesquisa
27.77%
Studies were carried out to test the hypothesis that the GSTM1 null phenotype at the mu (mu) class glutathione S-transferase 1 locus is associated with an increased predisposition to primary biliary cirrhosis. Starch gel electrophoresis was used to compare the prevalence of GSTM1 null phenotype 0 in patients with end stage primary biliary cirrhosis and a group of controls without evidence of liver disease. The prevalence of GSTM1 null phenotype in the primary biliary cirrhosis and control groups was similar; 39% and 45% respectively. In the primary biliary cirrhosis group all subjects were of the common GSTM1 0, GSTM1 A, GSTM1 B or GSTM1 A, B phenotypes while in the controls, one subject showed an isoform with an anodal mobility compatible with it being a product of the putative GSTM1*3 allele. As the GSTM1 phenotype might be changed by the disease process, the polymerase chain reaction was used to amplify the exon 4-exon 5 region of GSTM1 and show that in 13 control subjects and 11 patients with primary biliary cirrhosis, GSTM1 positive and negative genotypes were associated with corresponding GSTM1 expressing and non-expressing phenotypes respectively. The control subject with GSTM1 3 phenotype showed a positive genotype.

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender.

Heagerty, A.; Smith, A.; English, J.; Lear, J.; Perkins, W.; Bowers, B.; Jones, P.; Gilford, J.; Alldersea, J.; Fryer, A.; Strange, R. C.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em /01/1996 EN
Relevância na Pesquisa
27.74%
The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%)...

Population-specific GSTM1 copy number variation

Huang, R. Stephanie; Chen, Peixian; Wisel, Steve; Duan, Shiwei; Zhang, Wei; Cook, Edwin H.; Das, Soma; Cox, Nancy J.; Dolan, M. Eileen
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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As one of the major glutathione conjugation enzymes, GSTM1 detoxifies a number of drugs and xenobiotics. Its expression and activity have been shown to correlate both with cancer risks and drug resistance. Through a genome-wide association study, we identified a significant association between HapMap SNP rs366631 and GSTM1 expression. In this study, utilizing lymphoblastoid cell lines derived from International HapMap Consortium CEU and YRI populations, we designed and performed site-specific genotyping assays for both rs366631 and a highly homologous GSTM1 upstream site. Copy number variation (CNV) assays were performed for three different regions of the GSTM1 gene. We demonstrated that HapMap SNP rs366631 is a non-polymorphic site. The false genotyping call arises from sequence homology, a common GSTM1 region deletion and a non-specific genotyping platform used to identify the SNP. However, the HapMap call for rs366631 genotype is an indicator of GSTM1 upstream region deletion. Furthermore, this upstream deletion can be used as a marker of GSTM1 gene deletion. Using a novel GSTM1 CNV assay, we showed a population-specific CNV in this region upstream of the gene. More than 75% of the Caucasian (CEU) samples exhibit GSTM1 deletion and none contain two copies of GSTM1. In contrast...

Enhanced glutathione depletion, protein adduct formation, and cytotoxicity following exposure to 4-hydroxy-2-nonenal (HNE) in cells expressing human multidrug resistance protein-1 (MRP1) together with human glutathione S-transferase-M1 (GSTM1)

Rudd, Lisa P.; Kabler, Sandra L.; Morrow, Charles S.; Townsend, Alan J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.74%
4-hydroxy-2-nonenal (HNE) is one of the most reactive products of lipid peroxidation and has both cytotoxic and genotoxic effects in cells. Several enzymatic pathways have been reported to detoxify HNE, including conjugation by glutathione-S-transferases (GSTs). Removal of the resulting HNE-glutathione conjugate (HNE-SG) by an efflux transporter may required for complete detoxification. We investigated the effect of expression of GSTM1 and/or the ABC efflux transporter protein, multidrug-resistance protein-1 (MRP1), on HNE-induced cellular toxicity. Stably transfected MCF7 cell lines were used to examine the effect of GSTM1 and/or MRP1 expression on HNE-induced cytotoxicity, GSH depletion, and HNE-protein adduct formation. Co-expression in the MCF7 cell line of GSTM1 with MRP1 resulted in a 2.3-fold sensitization to HNE cytotoxicity (0.44-fold IC50 value relative to control) rather than the expected protection. Expression of either GSTM1 or MRP1 alone also resulted in slight sensitization to HNE cytotoxicity (0.79-fold and 0.71-fold decreases in IC50 values, respectively). Co-expression of GSTM1 and MRP1 strongly enhanced the formation of HNE-protein adducts relative to the non-expressing control cell line, whereas expression of either MRP1 alone or GSTM1 alone yielded similarly low levels of HNE-protein adducts to that of the control cell line. Glutathione (GSH) levels were reduced by 10–20% in either the control cell line or the MCF7/GSTM1 cell line with the same HNE exposure for 60 minutes. However...

Gender-Dependent Effect of GSTM1 Genotype on Childhood Asthma Associated with Prenatal Tobacco Smoke Exposure

Wu, Chih-Chiang; Ou, Chia-Yu; Chang, Jen-Chieh; Hsu, Te-Yao; Kuo, Ho-Chang; Liu, Chieh-An; Wang, Chih-Lu; Chuang, Chia-Ju; Chuang, Hau; Liang, Hsiu-Mei; Yang, Kuender D.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.74%
It remains unclear whether the GSTM1 genotype interacts with tobacco smoke exposure (TSE) in asthma development. This study aimed to investigate the interactions among GSTM1 genotype, gender, and prenatal TSE with regard to childhood asthma development. In a longitudinal birth cohort in Taiwan, 756 newborns completed a 6-year follow-up, and 591 children with DNA samples available for GSTM1 genotyping were included in the study, and the interactive influences of gender-GSTM1 genotyping-prenatal TSE on childhood asthma development were analyzed. Among these 591 children, 138 (23.4%) had physician-diagnosed asthma at 6 years of age, and 347 (58.7%) were null-GSTM1. Prenatal TSE significantly increased the prevalence of childhood asthma in null-GSTM1 children relative to those with positive GSTM1. Further analysis showed that prenatal TSE significantly increased the risk of childhood asthma in girls with null-GSTM1. Furthermore, among the children without prenatal TSE, girls with null-GSTM1 had a significantly lower risk of developing childhood asthma and a lower total IgE level at 6 years of age than those with positive GSTM1. This study demonstrates that the GSTM1 null genotype presents a protective effect against asthma development in girls...

Avaliação do polimorfismo de deleção de GSTT1 e GSTM1 na susceptibilidade ao diabetes mellitus tipo 2; Evaluation of GSTM1 and GSTT! deletion polymorphisms on type-2 diabetes mellitus susceptibility

Pinheiro, Denise da Silva
Fonte: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Biologia (ICB); Instituto de Ciências Biológicas - ICB (RG) Publicador: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Biologia (ICB); Instituto de Ciências Biológicas - ICB (RG)
Tipo: Dissertação Formato: application/pdf
POR
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37.79%
In the pathogenesis of type 2 diabetes mellitus (DM2), it is observed that the increased oxidative stress may contribute to decreased insulin production and destruction of pancreatic β cells. Individuals who have no activity of GSTM1 and GSTT1 isoforms may have an increased susceptibility to damage caused by reactive species to pancreatic β cells, since these cells express low levels of antioxidant enzymes. This case-control study aimed to analyze the genotypic profiles of the deletion polymorphism of GSTM1 and GSTT1 genes by molecular assays (conventional PCR and qPCR) to associate these polymorphisms with DM2 risk, considering that studies with this approach have not been conducted in Brazil. Data of clinical, laboratorial and demographic variables of 120 patients and 147 controls were obtained through interviews and information from medical charts (patients) or results of recent clinical and laboratory exams (controls). It was found that diabetic patients had a higher frequency of GSTT1-null genotype (29.2%) than non-diabetic subjects (12.2%), and those with the risk genotype have an increased predisposition to diabetes from approximately 3.2 times (p = 0.0004). However, there was no association of GSTM1-null with DM2 susceptibility. The analysis of the influence of GSTT1 deletion on clinical and biochemical changes in the case group showed that the risk genotype may contribute to the development of DM2 complications related to dyslipidemia...

Polymorphisms of CYP1A1 I462V and GSTM1 genotypes and lung cancer susceptibility in Mongolian

Fuhou Chang; Zhi-Xie Zhang; Jia Ma; Jun QI; Min-jie Wang; Qin Yin; Guang Wang
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
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27.8%
Aim: To study the genotype of cytochrome P450 1A1(CYP1A1) I462V and glutathions S-transferase M1( GSTM1) and the relationship of the genetic polymorphism of them with the susceptibility of lung cancer in Mongolia of China. Methods: Allele-specific PCR and a multiplex PCR were employed to identify the genotypes of I462V of CYP1A1 and GSTM1 in a case-control study of 210 lung cancer patients with bronchoscopy diagnosis and 210 matched controls free of malignancy. Results: The frequencies of the variant CYP1A1(Val/Val) genotypes and GSTM1(-) in lung cancer groups were higher than that in control groups (15.24% vs 7.4% and 56.67% vs 40.95% ). The individuals who carried with CYP1A1(Val/Val) or GSTM1(-) genotype had a significantly higher risk of lung cancer, the OR is 2.56 and 1.89 respectively. Stratified histologically the relative risk increased to 2.6 - fold when the patients carried with two valine alleles than the ones carried one valine allele in cases of SCC. GSTM1(-) genotype is the risk factor of SCC (OR=2.39) and AC(OR=2.16). The presence of at least one Val allele of CYP1A1 and GSTM1(-), the risk of lung cancer was increased, the OR was 4.15 for one Val allele and GSTM1(-) and 2.67 for two Val alleles and GSTM1 Considering ages and smoking status...

GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submitted to breast cancer screening

Aguiar,Ernestina Silva de; Giacomazzi,Juliana; Schmidt,Aishameriane Venes; Bock,Hugo; Saraiva-Pereira,Maria Luiza; Schuler-Faccini,Lavínia; Duarte Filho,Dakir; Santos,Pollyanna Almeida Costa dos; Giugliani,Roberto; Caleffi,Maira; Camey,Suzi Alves; Ashton
Fonte: Associação Brasileira de Pós -Graduação em Saúde Coletiva Publicador: Associação Brasileira de Pós -Graduação em Saúde Coletiva
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2012 EN
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Genetic polymorphisms in genes related to the metabolism of xenobiotics, such as genes of the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) superfamily have been associated with an increased risk for breast cancer (BC). Considering the high incidence of BC in the city of Porto Alegre in southern Brazil, the purpose of this study was to characterize genotypic and allelic frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1, and correlate these molecular findings with established risk factors for breast cancer including mammographic density, in a sample of 750 asymptomatic women undergoing mammographic screening. Molecular tests were performed using the multiplex polymerase chain reaction (PCR) for GSTM1 and GSTT1, and quantitative PCR for GSTP1 polymorphisms. Overall, the frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively. For GSTP1 polymorphism, genotypic frequencies were 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for Val/Val genotype, with an allelic frequency of 66% for the wild type allele in this population, similar to results of previous international publications. There was a statistically significant association between the combined GSTM1 and GSTT1 null genotypes (M-/T-) and mammographic density in post menopausal women (p = 0.031). When the GSTT1 null (T-) genotype was analyzed isolated...