Cadmium Exposure and Noncommunicable Diseases in Environmentally Exposed Brazilian Population: Cross-Sectional Study without Association of GSTP1 Polymorphism.

Cadmium (Cd) is a toxic metal which is harmful to humans and the environment. Cd levels and adverse effects may be associated with genetic polymorphisms in genes involved in its toxicokinetics. This study investigated Cd levels in 198 residents of a condominium in Rio de Janeiro, Brazil, built on industrial steel slag waste and the influence of glutathione S-transferase pi isoform 1 (GSTP1) rs1695 A>G polymorphism. Polymorphism was genotyped using a validated TaqMan assay; Cd levels were measured in blood (BCd) and urine (UCd) by graphite furnace atomic absorption spectrometry. Associations were evaluated by multiple logistic regression, odds ratios (ORs), and 95% confidence intervals (CIs). The mean Cd levels were 0.70 ± 0.20 µg L-1 (BCd), 0.58 ± 0.57 µg L-1 (UCd), and 0.61 ± 0.65 µg g-1 in urine corrected by creatinine (UcCd), and the Cd results were above tolerable levels (BCd > 0.5 µg L-1) in 87.4% of subjects. Higher blood Cd levels (>0.69 µg L-1) were associated with respiratory disease (OR = 2.4; 95%CI = 1.2-5.0), as almost 30% of people with respiratory diseases had higher Cd levels. The GSTP1 rs1695AA genotype frequency was 38.1%, and there were no significant differences between the SNP and Cd levels. High Cd levels and a high prevalence of diseases highlight the importance of implementing public policies and the continuous monitoring of this at-risk population.

The GSTP1 rs1695 Polymorphism Is Associated with Mercury Levels and Neurodevelopmental Delay in Indigenous Munduruku Children from the Brazilian Amazon.

Genetic polymorphisms may influence mercury (Hg) toxicity. The aims of this study were to evaluate individual factors, such as the presence of the GSTP1 rs1695 polymorphism, associated with internal Hg dose and child neurodevelopment in indigenous people from the Brazilian Amazon chronically exposed to Hg. Eighty-two indigenous children were clinically evaluated, hair Hg was measured, and the GSTP1 rs1695 polymorphism was genotyped. The mean age was 4.8 years, the median Hg was 5.5 µg/g, and 93.8% of children exceeded the safe limit (2.0 µg/g). Fish consumption was associated with Hg levels (p = 0.03). The GSTP1 rs1695 A>G polymorphism was in the Hardy-Weinberg equilibrium and the highest prevalence of the GSTP1 AA genotype (80%) was found in Sawré Aboy, which had the highest Hg levels (10 µg/g) among the studied villages. The Hg levels tended to increase over the years in males and in carriers of the GSTP1 AA genotype (0.69 µg/g and 0.86 µg/g, respectively). Nine children failed the neurodevelopmental test, all of whom had Hg > 2.0 µg/g, and 88.9% carried the GSTP1 AA or AG genotypes, previously associated with the highest internal Hg doses and neurocognitive disorders. The genetic counseling of this population is important to identify the individuals at greater risk for neurodevelopmental disorders resulting from chronic Hg exposure.

Association of genetic polymorphism of glutathione S-transferases with colorectal cancer susceptibility in snuff (Naswar) addicts / Associação de polimorfismo genético de glutationa S-transferase com suscetibilidade ao câncer colorretal em viciados em rapé (Naswar)

The current study aimed to investigate the relationship between polymorphisms in detoxifying (GSTM1, GSTT1, and GSTP1) genes and their association with colorectal cancer (CRC) in tobacco addicts of Pashtun ethnicity. Polymorphisms in the selected genes were genotyped in a case-control study consisting of 100 histologically confirmed male CRC patients and 100 birth-year and gender-matched healthy controls using the PCR−RFLP method. The GSTM1 null, and GSTT1 null genotypes were significantly contributed to the risk of CRC in the cases (OR= 3.131, 95% CI: 1.451−6.758, P = 0.004, and OR= 3.541, 95% CI: 1.716−7.306, P = 0.001, respectively), whereas the association observed for GSTP1 Val/Val (1.139, 95% CI: 0.356−3.644, P = 0.826) did not show statistical significance. The combined GSTM1 null and GSTT1 null showed a 41-fold increased risk (95% CI: 4.945−351.950, P = 0.001), while, the combined GSTM1 null and GSTP1 Ile/Val or Val/Val variant genotypes exhibited about 3-fold (95% CI: 1.196−7.414, P = 0.019) increased risk to CRC. Similarly, the combined GSTT1 null and GSTP1 Ile/Val or Val/Val variant genotypes showed about a 3-fold (95% CI: 1.285−8.101, P = 0.013) increased risk of CRC. In the combination of three GST genotypes, the GSTM1 null, GSTT1 null, and GSTP1 Ile/Val or Val/Val variant genotypes demonstrated a more than a 22-fold (95% CI: 2.441−212.106, P = 0.006) increased risk of CRC. Our findings suggest that GSTM1 and GSTT1 polymorphism and its combination with GSTP1 may be associated with CRC susceptibility in the Naswar addicted Pashtun population of Khyber Pakhtunkhwa, Pakistan.

O presente estudo teve como objetivo investigar a relação entre polimorfismos em genes desintoxicantes (GSTM1, GSTT1 e GSTP1) e sua associação com câncer colorretal (CCR) em tabagistas da etnia pashtun. Os polimorfismos nos genes selecionados foram genotipados em um estudo de caso-controle composto por 100 pacientes do sexo masculino com CCR, confirmados histologicamente, e 100 controles saudáveis, ​​pareados por ano de nascimento e sexo usando o método PCR-RFLP. Os genótipos GSTM1 nulo e GSTT1 nulo contribuíram significativamente para o risco de CCR nos casos (OR = 3,131, IC 95%: 1,451-6,758, P = 0,004; OR = 3,541, IC 95%: 1,716-7,306, P = 0,001, respectivamente), enquanto a associação observada para GSTP1 Val/Val (1,139, IC 95%: 0,356-3,644, P = 0,826) não apresentou significância estatística. O GSTM1 nulo e o GSTT1 nulo combinados mostraram um risco 41 vezes maior (IC 95%: 4,945-351,950, P = 0,001) para CCR, enquanto os genótipos GSTM1 nulo e GSTP1 Ile/Val ou Val/Val combinados apresentaram risco cerca de 3 vezes maior (IC 95%: 1,196-7,414, P = 0,019) para CCR. Da mesma forma, os genótipos combinados GSTT1 nulo e GSTP1 Ile/Val ou Val/Val tiveram um risco para CRC cerca de 3 vezes maior (95% CI: 1,285-8,101, P = 0,013). Na combinação de três genótipos GST, os genótipos GSTM1 nulo, GSTT1 nulo e GSTP1 Ile/Val ou Val/Val apresentaram um risco 22 vezes maior (IC 95%: 2,441-212,106, P = 0,006) para CRC. Nossos achados sugerem que o polimorfismo GSTM1 e GSTT1 e sua combinação com GSTP1 podem estar associados à suscetibilidade ao CRC da população pashtun de Khyber Pakhtunkhwa, Paquistão, viciada em Naswar.

Promoter hypermethylation of RARB and GSTP1 genes in plasma cell-free DNA as breast cancer biomarkers in Peruvian women.

BACKGROUND: Promoter hypermethylation is one of the enabling mechanisms of hallmarks of cancer. Tumor suppressor genes like RARB and GSTP1 have been reported as hypermethylated in breast cancer tumors compared with normal tissues in several populations. This case-control study aimed to determine the association between the promoter methylation ratio (PMR) of RARB and GSTP1 genes (separately and as a group) with breast cancer and its clinical-pathological variables in Peruvian patients, using a liquid biopsy approach. METHODS: A total of 58 breast cancer patients and 58 healthy controls, matched by age, participated in the study. We exacted cell-free DNA (cfDNA) from blood plasma and converted it by bisulfite salts. Methylight PCR was performed to obtain the PMR value of the studied genes. We determined the association between PMR and breast cancer, in addition to other clinicopathological variables. The sensitivity and specificity of the PMR of these genes were obtained. RESULTS: A significant association was not found between breast cancer and the RARB PMR (OR = 1.90; 95% CI [0.62-6.18]; p = 0.210) or the GSTP1 PMR (OR = 6.57; 95% CI [0.75-307.66]; p = 0.114). The combination of the RARB + GSTP1 PMR was associated with breast cancer (OR = 2.81; 95% CI [1.02-8.22]; p = 0.026), controls under 50 years old (p = 0.048), patients older than 50 (p = 0.007), and postmenopausal (p = 0.034). The PMR of both genes showed a specificity of 86.21% and a sensitivity of 31.03%. CONCLUSION: Promoter hypermethylation of RARB + GSTP1 genes is associated with breast cancer, older age, and postmenopausal Peruvian patients. The methylated promoter of the RARB + GSTP1 genes needs further validation to be used as a biomarker for liquid biopsy and as a recommendation criterion for additional tests in asymptomatic women younger than 50 years.

Chronic Mercury Exposure and GSTP1 Polymorphism in Munduruku Indigenous from Brazilian Amazon.

Genetic polymorphisms may be involved with mercury levels and signs and symptoms of intoxication from this exposure. Therefore, the aims were to describe the frequency of the GSTP1 polymorphism and to evaluate its effects on mercury levels and neurological signs in three Munduruku indigenous villages in the Brazilian Amazon. One-hundred-and-seven indigenous (over 12 years old) were included and genotyped (rs1695) using a TaqMan validated assay. Then, associations were evaluated by binary logistic regression, using odds ratios (OR) and 95% confidence intervals (CI). Mean age was 27.4 ± 13.9 years old, 52.3% were male, mean hair mercury concentration was 8.5 ± 4.3, exceeding the reference limit (≥6.0 µg/g), and were different among the three villages: 13.5 ± 4.6 µg/g in Sawré Aboy, 7.4 ± 2.3 µg/g in Poxo Muybu and 6.9 ± 3.5 µg/g in Sawré Muybu. The minor allele frequency of GSTP1 G was significantly different among the villages: 57% Sawré Muybu, 21% Poxo Muybu and 15% Sawré Aboy. Finally, after adjustment, GSTP1 GG and GA genotypes were associated with lower levels of Hg (OR = 0.13; CI95% = 0.03-0.49) and abnormal somatosensory signs (OR = 3.7; 95%IC = 1.5-9.3), respectively. In conclusion, monitoring this population is imperative to identify individuals at higher risk of developing signs of chronic mercury exposure based on the genetic profile.

Dietary polyphenols and their relationship to the modulation of non-communicable chronic diseases and epigenetic mechanisms: A mini-review.

Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

Influence of GSTP1 rs1695 polymorphism on survival in male patients' amyotrophic lateral sclerosis: a genetic association study in Brazilian population.

BACKGROUND: Glutathione S-transferase Pi (GSTP1) enzyme has a major antioxidant effect on the central nervous system (CNS), where it acts against oxidative damage, an established risk factor for amyotrophic lateral sclerosis (ALS). Hence, the purpose of this study was to evaluate a possible relationship between GSTP1 rs1695 polymorphism and the survival rate of male ALS patients, which is the gender more affected by the disease. METHODS AND RESULTS: A case-control study was performed with 56 male ALS patients and 70 healthy male individuals from Midwestern Brazil, which were age-adjusted. GSTP1 rs1695 polymorphism molecular analysis was carried out with restriction fragment length polymorphism. The relationship between ALS patients and GSTP1 rs1695 polymorphism was analyzed using cumulative survival rate as the major outcome, where differences in survival were evaluated through the log-rank test. Our results revealed that mutant genotype (G/G) did not influence the cumulative survival rate of male ALS patients regarding the age of diagnosis (p = 0.5) and time from symptom to diagnosis (p = 0.3). On the other hand, mutant carriers exhibited a significant survival of fewer than 25 months compared to A/A and A/G genotypes that survive more than 100 months (p = 7-E10) in comparison with symptom onset to outcome (p = 0.00006). CONCLUSIONS: In summary, our findings revealed that mutant genotype carriers' male patients had a reduced lifetime, which probably may be resulted from oxidative stress exposure in CNS.

Biochemical and genotoxic effects in women exposed to pesticides in Southern Ecuador.

Toxicity refers to the potential of a substance such as a pesticide to cause damage to the structure or functions of an exposed organism. Pesticides can lead to harmful biological effects in exposed animals and their offspring over the medium and long term. They can affect the immunological, nervous, endocrine, and reproductive systems. DNA damage has also been linked to exposure to pesticides, and this damage can cause abortions, degenerative diseases, and cancer. The aim of this work was to establish whether women who are indirectly exposed to pesticides exhibit a compromised health status, including genotoxic effect. Women exposed indirectly to pesticides in Chimchanga and Colaisaca in the south of Ecuador underwent hematological and biochemical tests and micronucleus assay in buccal cells. The subjects were also genotyped for GSTM1, GSTT1, GSTP1, and PON1 polymorphisms, which can modify an individual's capacity to metabolize pesticides and relation with damage of DNA. The study revealed hepatic toxicity in Colaisaca women (AST and ALT) and an increase in the rate of micronucleus (MN) in Colaisaca individuals. In addition, genetic polymorphisms in PON1 and GSTP1 showed effects of modulating the frequency of karyolytic cells, karyorrhectic cells, and condensed chromatin cells.

Contribution of the GSTP1 c.313A>G variant to hearing loss risk in patients exposed to platin chemotherapy during childhood.

BACKGROUND AND AIM: Ototoxicity is a potential adverse effect of chemotherapy with platin drugs, such as cisplatin and carboplatin, in children. Hearing loss (HL) affecting frequencies below 4 kHz can compromise speech perception. The aim of this study was to investigate whether genetic variants previously implicated in ototoxicity are associated with HL overall and HL below 4 kHz in pediatric oncology patients treated with cisplatin or carboplatin. MATERIALS AND METHODS: Patients given cisplatin or carboplatin for a pediatric cancer at least 5 years prior to the start of the study were enrolled. The patients underwent comprehensive audiological evaluations and genotyping to detect the presence of the GJB2 c.35delG, GSTP1 c.313A>G, and MT-RNR1 m.1555A>G polymorphisms. RESULTS: HL was identified in 31/61 patients (50.8%), including 28/42 treated with cisplatin (66.6%) and 3/19 treated with carboplatin (15.8%). HL was associated with higher mean doses of cisplatin (p = .002) and carboplatin (p = .010). The c.313A>G variant of GSTP1 (heterozygous or homozygous) was detected in 31/61 patients (50.8%). An association between this variant allele and HL involving frequencies ≤ 4 kHz was identified (p = .020; 10-fold vs. non-carriers). No associations with HL were observed for GJB2 or MT-RNR1 gene variants. CONCLUSION: The GSTP1 c.313A>G variant may increase the risk of low-frequency HL in pediatric oncology patients treated with cisplatin or carboplatin chemotherapy.

Knockdown of Host Antioxidant Defense Genes Enhances the Effect of Glucantime on Intracellular Leishmania braziliensis in Human Macrophages.

Leishmaniasis is a neglected tropical disease that affects millions of people worldwide and represents a major public health problem. Information on protein expression patterns and functional roles within the context of Leishmania-infected human monocyte-derived macrophages (MDMs) under drug treatment conditions is essential for understanding the role of these cells in leishmaniasis treatment. We analyzed functional changes in the expression of human MDM genes and proteins during in vitro infection by Leishmania braziliensis and treatment with Glucantime (SbV), using quantitative PCR (qPCR) arrays, Western blotting, confocal microscopy, and small interfering RNA (siRNA) human gene inhibition assays. Comparison of the results from gene transcription and protein expression analyses revealed that glutathione S-transferase π1 (GSTP1), glutamate-cysteine ligase modifier subunit (GCLM), glutathione reductase (GSR), glutathione synthetase (GSS), thioredoxin (TRX), and ATP-binding cassette, subfamily B, member 5 (ABCB5), were strongly upregulated at both the mRNA and protein levels in human MDMs that were infected and treated, compared to the control group. Subcellular localization studies showed a primarily phagolysosomal location for the ABCB5 transporter, indicating that this protein may be involved in the transport of SbV By inducing a decrease in L. braziliensis intracellular survival in THP-1 macrophages, siRNA silencing of GSTP1, GSS, and ABCB5 resulted in an increased leishmanicidal effect of SbV exposure in vitro Our results suggest that human MDMs infected with L. braziliensis and treated with SbV express increased levels of genes participating in antioxidant defense, whereas our functional analyses provide evidence for the involvement of human MDMs in drug detoxification. Therefore, we conclude that GSS, GSTP1, and ABCB5 proteins represent potential targets for enhancing the leishmanicidal activity of Glucantime.

Study of the influence of genes related to muscle oxidative processes on beef color.

The biochemical bases of meat color are determined by the concentration and redox state of myoglobin, hemoglobin, cytochromes, and other pigments. Post-mortem depletion of cellular oxygen results in oxidative stresses that consume NADH and affects reducing activity, while enzymatic detoxification influences the cellular oxidative processes, both affecting meat color. The aim of this work was to study the influence of several genes related to cellular oxidative processes that could affect CIELAB meat color parameters. The study was performed in steers that received a grass-based diet combined with grain, hays and silages. Results suggest a possible link between colorimetric parameters (a*, b* and chroma) and SNPs in the GSTP1 gene (P<0.05). Although the influence of the enzymes, encoded by GSTP1 gene, on meat color has been proposed previously at biochemical level and protein expression level, further association studies in different populations and functional studies of proteins are needed to confirm the genetic determination of that gene on meat color.

Unraveling Brazilian Indian population prostate good health: clinical, anthropometric and genetic features

Purpose To compare dietary, lifestyle, clinical, anthropometric, genetic and prostatic features of Brazilian Indians and non-Indians (Amazon). Methods 315 men, 228 Indians and 89 non-Indians, ≥40 years old were submitted to digital rectal examination, serum prostate specific antigen (PSA), testosterone, TP53 and GSTP1 genotyping, anthropometric, lifestyle, dietary, personal and familial medical history. Prostatic symptoms were evaluated with the International Prostate Symptom Score (IPSS). Results Macuxis and Yanomamis represented 43.6% and 14.5% of Indians respectively who spontaneously referred no prostate symptoms. Mean IPSS was 7, range 3-19, with only 15% of moderate symptoms (score 8-19); Mean age was 54.7 years, waist circumference 86.6 cm, BMI 23.9 kg/m2. Yanomamis presented both lower BMI (21.4 versus 24.8 and 23.3, p=0,001) and prostate volume than Macuxis and “other ethnic groups” (15 versus 20, p=0.001). Testosterone (414 versus 502 and 512, p=0.207) and PSA (0.48 versus 0.6 and 0.41, p=0.349) were similar with progressive PSA increase with aging. Val/Val correlated with lower PSA (p=0.0361). Indians compared to control population presented: - TP53 super representation of Arg/Arg haplotype, 74.5% versus 42.5%, p<0.0001. -GSTP1 Ile/Ile 35.3% versus 60.9%; Ile/Val 45.9% versus 28.7%; Val/Val 18.8% versus 10.3%; p=0.0003. Conclusions Observed specific dietary, lifestyle, anthropometric and genetic profile for TP53 and GSTP1 may contribute to Brazilian Indian population prostate good health. .

Distribution of GSTM1, GSTT1, GSTP1 and TP53 disease-associated gene variants in native and urban Venezuelan populations.

The contemporary Venezuelan population is the product of major admixture process across various historical events, which has provided it a particular genetic background. The aim of this study concerns the analysis of glutathione S-transferase (GST) GSTM1, GSTP1 and GSTT1 genetic variants and five polymorphisms at the TP53 gene, which are related to cancer susceptibility, in an urban/admixed population and five Amerindian tribes (Bari, Panare, Pemon, Warao and Wayuu) from Venezuela. Genotyping was carried out in 120 individuals from an urban sample and 188 Amerindians. The analysis performed on TP53 haplotype and GST allele distribution showed a close correlation for Pemon and Warao populations, while Bari group appears isolated from the other populations. GSTT1 null variant frequency in our admixed (11%) and native samples (0.0-11.4%) was lower when compared with Caucasians, Africans and Asians. Frequency of the GSTP1*Val cancer-associated allele found in Bari (88.6%) and Panare (63.0%) is of the highest so far reported. Fourteen TP53 haplotypes were observed in the admixed populations, whereas only 3 to 5 in Amerindians. To our knowledge this is the first report of GST polymorphisms and TP53 haplotype distribution in Venezuelans. The distribution of most of analyzed polymorphisms in the urban sample is consistent with the admixed origin of the present-day population of Venezuela. While, the inter-ethnic variations in genetic polymorphisms found in Native American tribes seem to be the result of the influence of demographic factors. These results provide additional data for undertaking ethnographic and disease association studies in Venezuela.

Glutathione S-transferase P1 mRNA expression in plasma cell disorders and its correlation with polymorphic variants and clinical outcome.

BACKGROUND: Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in detoxification of carcinogens. GSTP1 gene overexpression has been observed in a variety of human cancers but there are no studies in plasma cell disorders. The aim of this study was to examine GSTP1 mRNA expression level in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). In addition, we have determined GSTP1 polymorphic variants in order to estimate MM risk and their relationship with the expression level. Results were also correlated with laboratory parameters and clinical outcome. METHODS: Bone marrow mononuclear cells from 125 patients with plasma cell disorders were studied. Peripheral blood samples of 110 age and sex matched healthy controls were also evaluated. Real-Time Quantitative RT-PCR and PCR-RFLP assays were used. RESULTS: Upregulation of GSTP1 was observed in 37.7% MM and in 22.6% MGUS patients. A significant increase of GSTP1 expression in MM with respect to MGUS was detected (p=0.0427). Most MM patients that achieved complete remission had low transcription levels (77.8%) compared to those who did not reach this condition (44.4%) (p=0.0347). GSTP1 heterozygous carriers showed reduced expression compared to those with homozygous wild type genotype (p=0.0135). CONCLUSION: Our findings suggest, for the first time, a role for GSTP1 expression in development and/or progression of plasma cell disorders, and a probable influence of functional capacity of the enzyme on clinical outcome. These results and those of the literature support GSTP1 as an interesting tumor marker and a potential therapeutic target.

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

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, the association with mammographic density in post menopausal women and in the overall sample was also statistically significant (p = 0.023 and p = 0.027, respectively). These findings suggest an association of GSTM1 and GSTT1 null genotypes with mammographic density.

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 = 0,031). Quando analisamos isoladamente o genótipo GSTT1 nulo (T-) também encontramos uma associação significativa com a densidade mamográfica nas mulheres pós-menopáusicas (p = 0,027) e na amostra total. Estes achados sugerem uma associação dos genótipos (T-/M-) nulos com densidade mamográfica.

Óxido nítrico, GSTP-1 e p53: qual o papel desses biomarcadores nas lesões prostáticas do cão? / Nitric oxide, GSTP-1 and p53: what's the role of these biomarkers in dogïs prostate lesions?

Confeccionou-se um microarranjo de tecido (TMA) com 146 amostras de lesões prostáticas caninas. Este continha 17,2 por cento de hiperplasia prostática benigna (HPB), 32,4 por cento de atrofia inflamatória proliferativa (PIA), 2,6 por cento de prostatite, 8,6 por cento de focos de neoplasia intraepitelial prostática (PIN), 29,1 por cento de carcinomas e 9,3 por cento de próstatas normais. Cortes histológicos sequenciais foram feitos e utilizados para reação de imunoistoquímica com os anticorpos primários anti-p-53, anti-NOS-2 e anti-GSTP. Avaliou-se de cada core o escore de células marcadas para cada anticorpo utilizado. Os resultados foram tabulados por grupo diagnóstico e submetidos ao teste Tuckey. Os carcinomas prostáticos do cão e a PIA apresentaram maior número de amostras (41) com mais de 75 por cento das células positivas para NOS-2, demonstrando a influência do estresse oxidativo no desenvolvimento dessas lesões. As próstatas normais e as afecções desta glândula, HPB, PIA, PIN, prostatite e carcinoma, expressaram a proteína GSTP-1, o que conferiu proteção ao tecido prostático canino a danos oxidativos. A proteína p53 estava presente em todas as amostras estudadas, incluindo o tecido prostático normal, porém as lesões prostáticas apresentaram maior número de amostras com escores mais elevados de marcação (escores três e quatro), presente em 95 por cento dos focos de PIA e carcinoma. Concluiu-se que o aumento de expressão de óxido nítrico nas lesões prostáticas no cão e a expressão de GSTP-1 podem ter protegido o tecido prostático canino e que a expressão de p53 foi positiva e uniforme nas próstatas normais e com lesões hiperplásicas e displásicas.(AU)

A tissue microarray (TMA) with 149 samples of canine prostatic lesions contained 17.2 percent benign prostatic hyperplasia (BPH), 32.4 percent proliferative inflammatory atrophy (PIA), 2.6 percent prostatitis, 8.6 percent foci prostatic intraepithelial neoplasia (PIN), 29.1 percent carcinomas and 9.3 percent normal prostates. Sequential histological sections were made and used for immunohistochemistry reaction with primary antibodies anti p-53, anti-NOS-2 and anti-GSTP. The score for each antibody employed was evaluated. The results were tabulated by diagnostic group and subjected to Tuckey test. Prostatic carcinomas and PIA had a higher number of samples (41) with over 75 percent of cells positive for NOS-2, demonstrating the influence of oxidative stress in the development of these lesions. The prostates of normal dogs, as well as the disorders of this gland (BPH, PIA, PIN, prostatitis and carcinoma), expressed GSTP-1 protein, which gives protection to the canine prostate tissue against oxidative damage. The p53 protein was present in all samples studied, including normal prostate tissue, but the prostatic lesions had a higher number of samples with higher scores (more than 50 percent of positive cells), in 95 percent of foci of PIA and carcinoma. It was found that an increased expression of NO in prostatic lesions of dogs and that the expression of GSTP-1 can protect the canine prostate tissue, which would contribute to the low frequency of prostate adenocarcinoma in this species. The expression of p53 was positive in all lesions as well as the in normal prostate.(AU)

Óxido nítrico, GSTP-1 e p53: qual o papel desses biomarcadores nas lesões prostáticas do cão? / Nitric oxide, GSTP-1 and p53: what's the role of these biomarkers in dog´s prostate lesions?

Confeccionou-se um microarranjo de tecido (TMA) com 146 amostras de lesões prostáticas caninas. Este continha 17,2 por cento de hiperplasia prostática benigna (HPB), 32,4 por cento de atrofia inflamatória proliferativa (PIA), 2,6 por cento de prostatite, 8,6 por cento de focos de neoplasia intraepitelial prostática (PIN), 29,1 por cento de carcinomas e 9,3 por cento de próstatas normais. Cortes histológicos sequenciais foram feitos e utilizados para reação de imunoistoquímica com os anticorpos primários anti-p-53, anti-NOS-2 e anti-GSTP. Avaliou-se de cada core o escore de células marcadas para cada anticorpo utilizado. Os resultados foram tabulados por grupo diagnóstico e submetidos ao teste Tuckey. Os carcinomas prostáticos do cão e a PIA apresentaram maior número de amostras (41) com mais de 75 por cento das células positivas para NOS-2, demonstrando a influência do estresse oxidativo no desenvolvimento dessas lesões. As próstatas normais e as afecções desta glândula, HPB, PIA, PIN, prostatite e carcinoma, expressaram a proteína GSTP-1, o que conferiu proteção ao tecido prostático canino a danos oxidativos. A proteína p53 estava presente em todas as amostras estudadas, incluindo o tecido prostático normal, porém as lesões prostáticas apresentaram maior número de amostras com escores mais elevados de marcação (escores três e quatro), presente em 95 por cento dos focos de PIA e carcinoma. Concluiu-se que o aumento de expressão de óxido nítrico nas lesões prostáticas no cão e a expressão de GSTP-1 podem ter protegido o tecido prostático canino e que a expressão de p53 foi positiva e uniforme nas próstatas normais e com lesões hiperplásicas e displásicas.

A tissue microarray (TMA) with 149 samples of canine prostatic lesions contained 17.2 percent benign prostatic hyperplasia (BPH), 32.4 percent proliferative inflammatory atrophy (PIA), 2.6 percent prostatitis, 8.6 percent foci prostatic intraepithelial neoplasia (PIN), 29.1 percent carcinomas and 9.3 percent normal prostates. Sequential histological sections were made and used for immunohistochemistry reaction with primary antibodies anti p-53, anti-NOS-2 and anti-GSTP. The score for each antibody employed was evaluated. The results were tabulated by diagnostic group and subjected to Tuckey test. Prostatic carcinomas and PIA had a higher number of samples (41) with over 75 percent of cells positive for NOS-2, demonstrating the influence of oxidative stress in the development of these lesions. The prostates of normal dogs, as well as the disorders of this gland (BPH, PIA, PIN, prostatitis and carcinoma), expressed GSTP-1 protein, which gives protection to the canine prostate tissue against oxidative damage. The p53 protein was present in all samples studied, including normal prostate tissue, but the prostatic lesions had a higher number of samples with higher scores (more than 50 percent of positive cells), in 95 percent of foci of PIA and carcinoma. It was found that an increased expression of NO in prostatic lesions of dogs and that the expression of GSTP-1 can protect the canine prostate tissue, which would contribute to the low frequency of prostate adenocarcinoma in this species. The expression of p53 was positive in all lesions as well as the in normal prostate.

Mutational analysis of xenobiotic metabolizing genes (CYP1A1 and GSTP1) in sporadic head and neck cancer patients.

CYP1A1 is the phase I enzyme that detoxifies the carcinogen or converts it into a more electrophilic form, metabolized by phase II enzymes like GSTP1. These detoxifying genes have been extensively studied in association with head and neck cancer (HNC) in different ethnic groups worldwide. The current study was aimed at screening genetic polymorphisms of genes CYP1A1 and GSTP1 in 388 Pakistani HNC patients and 150 cancer-free healthy controls, using PCR-SSCP. No already known variants of either gene were found, however a novel frameshift mutation due to insertion of T (g.2842_2843insT) was observed in the CYP1A1 gene. A statistically significant number (5.4%) of HNC cases, with the mean age of 51.75 (±15.7) years, presented this frameshift mutation in the conserved domain of CYP1A1. Another novel substitution mutation in was found in the GSTP1 gene, presenting TA instead of AG. The g.2848A > T polymorphism causes a leucine-to-leucine formation, whereas g.2849G > A causes alanine-to-threonine formation at amino acid positions 166 and 167, respectively. These exonic mutations were found in 9.5% of the HNC patients and in none of the controls. In addition, two intronic deletions of C (g.1074delC and g.1466delC) were also found in 11 patients with a mean age of 46.2 (±15.6) years. In conclusion, accumulation of mutations in genes CYP1A1 and GSTP1 appears to be associated with increased risk of developing HNC, suggesting that mutations in these genes may play a role in the etiology of head and neck cancer.

Mutational analysis of xenobiotic metabolizing genes (CYP1A1 and GSTP1) in sporadic head and neck cancer patients

CYP1A1 is the phase I enzyme that detoxifies the carcinogen or converts it into a more electrophilic form, metabolized by phase II enzymes like GSTP1. These detoxifying genes have been extensively studied in association with head and neck cancer (HNC) in different ethnic groups worldwide. The current study was aimed at screening genetic polymorphisms of genes CYP1A1 and GSTP1 in 388 Pakistani HNC patients and 150 cancer-free healthy controls, using PCR-SSCP. No already known variants of either gene were found, however a novel frameshift mutation due to insertion of T (g.2842_2843insT) was observed in the CYP1A1 gene. A statistically significant number (5.4 percent) of HNC cases, with the mean age of 51.75 (±15.7) years, presented this frameshift mutation in the conserved domain of CYP1A1. Another novel substitution mutation in was found in the GSTP1 gene, presenting TA instead of AG. The g.2848A > T polymorphism causes a leucine-to-leucine formation, whereas g.2849G > A causes alanine-to-threonine formation at amino acid positions 166 and 167, respectively. These exonic mutations were found in 9.5 percent of the HNC patients and in none of the controls. In addition, two intronic deletions of C (g.1074delC and g.1466delC) were also found in 11 patients with a mean age of 46.2 (±15.6) years. In conclusion, accumulation of mutations in genes CYP1A1 and GSTP1 appears to be associated with increased risk of developing HNC, suggesting that mutations in these genes may play a role in the etiology of head and neck cancer.

Cáncer gástrico y genes detoxificadores en una población colombiana / Gastric cancer and detoxifying genes in a colombian population

El objetivo fue establecer si hay asociación entre el cáncer gástrico (CG) y los polimorfismos desfavorables de los genes desintoxicadores GSTM1, GSTP1 y GSTT1. A la vez, se exploró si el hábito del tabaquismo, el consumo de alcohol y el nivel socioeconómico también interactúan como factores de riesgo en una población colombiana con alta incidencia de CG. Participaron 87 pacientes afectados por CG e igual número de controles del mismo grupo poblacional del departamento de Caldas. Todos fueron genotipíficados por medio de PCR para los polimorfismos GSTM1-nulo, GSTP1-val y GSTT1-nulo. Se colectó información acerca del tabaquismo, consumo de alcohol y nivel socioeconómico. Los resultados encontrados sugieren que es factor de riesgo significativo portar el genotipo GSTT1-nulo o el alelo GSTP1-val y pertenecer a los niveles socioeconómicos bajo o medio. También se detectó un interacción significativa entre el tabaquismo, el nivel socioeconómico bajo y el riesgo a CG. En conclusión, se evidencia interacción significativa entre ambiente-gen, particularmente entre el genotipo GSTT1-nulo, el alelo GSTP1-val, el nivel socioeconómico bajo, el tabaquismo y el riesgo a desarrollar CG en la población de esta región colombiana.

The objective was to establish whether there are associations between gastric cancer (GC) and unfavorable polymorphisms in GSTM1, GSTP1 and GSTT1 detoxifying genes. Simultaneously interactions of smoking habits, alcohol consumption and socioeconomic levels were investigated as possible risk factors in a Colombian population with a high incidence of GC. 87 patients affected by GC and 87 controls from the same population group in the Department of Caldas participated in the research. All patients were genotyped by PCR for GSTM1-null, GSTP1-val and GSTT1-null polymorphisms. Information about tobacco smoking, alcohol consumption and socioeconomic levels was collected. Results suggest that the GSTM1-nul genotype and GSTP1-val allele are significant risk factors as are low and medium socioeconomic levels. Significant interaction between tobacco smoking, low socioeconomic levels and GC risks were also detected. To conclude, there is significant interaction between environment and genes, particularly between the GSTT1-nulle genotype and GSTP1-val allele and low socioeconomic levels, tobacco smoking and the risk of GC development within this Colombian region’s population.