GSTT1 Research Articles

Deletion polymorphism of glutathione S-transferases genes (GSTT1, GSTM1) in patients with breast cancer in Primorye region

Background. Breast cancer (BC) refers to multifactorial polygenic diseases that occur as a result of the combined interaction of genetic and environmental factors. Glutathione-mediated detoxification is of key importance in ensuring the resistance of body cells to the damaging effect of xenobiotics.Objective: to study the prevalence of deletion polymorphisms of the GSTM1 and GSTT1 genes and to establish their influence on the formation of cancer risk in patients with BC in the Primorye region (Russia).Materials and methods. The study involved 176 women with BC, aged 23 to 79 years (mean age 48 ± 13 years) and 66 conditionally healthy individuals without cancer. The detection of deletion (null) genotypes of the GSTM1 and GSTT1 was carried out using multiplex PCR followed by analysis of the melting curves of the reaction products.Results. The frequency of GSTT1-0 genotype among BC patients was higher than in the control group (14.77 % versus 6.06 %), significantly exceeding the indicators in the control group by more than 2.5 times (p <0.1), indicating an association between the carriage of the GSTT1-0 genotype and the risk of developing BC. At the same time, the frequencies of the GSTM1-0 genotype in the study groups were comparable; no statistically significant association with the risk of developing BC was found.Conclusions. Homozygous deletion of GSTT1 (GSTT1-0) can potentially be considered as a low-penetrant risk factor for developing BC in the population of Primorye region.

The Relationship Between GSTT1, GSTM1, GSTO1, GSTP1 and MTHFR Gene Polymorphisms and DNA Damage of BRCA1 and BRCA2 Genes in Arsenic-Exposed Workers.

To investigate the associations between genetic polymorphisms of GSTT1, GSTM1, GSTO1, GSTP1 and MTHFR genes and the DNA damage levels of BRCA1 and BRCA2 genes. Peripheral blood samples were used to measure DNA damage levels and genetic polymorphisms, and urine samples were collected to analyze arsenic metabolites in 79 arsenic-exposed workers and 24 non-arsenic-exposed workers. The BRCA1 and BRCA2 damage levels in exposure group were significantly higher than that in control group. Significant associations were detected between GSTT1 and GSTO1 polymorphisms and DNA damage levels of BRCA1 and BRCA2 genes in subjects (P < 0.05). Our findings suggest that the DNA damage levels of BRCA1 and BRCA2 genes may modulate by genetic variations of GSTT1 and GSTO1 when individuals are exposed to carcinogens, such as arsenic.

Impact of xenobiotic-metabolizing gene polymorphisms on breast cancer risk in South Indian women.

Functional variants of the xenobiotic-metabolizing genes (XMG) might modulate breast cancer (BC) risk by altering the rate of metabolism and clearance of myriad types of potent carcinogens from the breast tissue. Despite mounting evidence on the role of XMG variants on BC risk, the current knowledge regarding their influence on BC development is still fragmentary. The present study examined the candidate genetic variants in CYP1A1, NQO1, GST-T1, GST-M1, and GST-P1 in 1002 subjects (502 BC patients and 500 disease-free women). PCR-RFLP was employed to genotype the mono-nucleotide variation in CYP1A1, NQO1, and GST-P1, and allele-specific PCR was used to detect the deletion polymorphism in GST-T1 and GST-M1 genes. Regarding CYP1A1-M1 polymorphism, the heterozygous TC and mutant CC genotype conferred 1.47-fold (95% CI 1.13-1.91, p = 0.004) and 1.84-fold (95% CI 1.17-2.91, p = 0.009) elevated risk of BC. GST-T1 null genotype was associated with increased BC risk (OR 1.47; 95% CI 1.02-2.11, p = 0.037). For the NQO1 C609T variant, the mutant T allele was associated with BC risk with an odds ratio of 1.22 (95% CI 1.02-1.48, p = 0.034). Combinatorial analysis indicated that the presence of NQO1*2 (CT), CYP1A1-M1 (CC), and GST-P1 rs1695 (AG) genotypes conferred 16.7-fold elevated risk of BC (95% CI 3.65-76.85; p < 0.001). Moreover, GST-M1 null genotype was associated with the development of larger primary breast tumors. Xenobiotic-metabolizing gene polymorphisms may play a crucial role in mammary carcinogenesis in South Indian women.

ROLE OF GENETIC PREDISPOSITION, GENE POLYMORPHISM OF GLUTATHIONE-S-TRANSFERASE (GSTT1, GSTM1, GSTP1) AND SOME ADVERSE FACTORS IN DEVELOPMENT OF BRONCHIAL ASTHMA IN CHILDREN - RESIDENTS OF RADIOACTIVELY CONTAMINATED AREAS.

to determine the influence of hereditary predisposition, polymorphism of GSTT1, GSTM1, GSTP1 genes andenvironmental factors on the development of bronchial asthma in children - residents of radioactively contaminat-ed areas. School-age children-residents of radioactively contaminated areas with bronchial asthma,and those without clinical signs of respiratory pathology were examined. Genetic, medical, biological and social riskfactors were determined based on the study of anamnestic data and medical records. Ventilation lung capacity wasassessed by the method of computer spirometry. Molecular genetic studies were carried out using polymerase chainreaction (PCR) and restriction fragment length polymorphism (RFLP) for further analysis. Molecular genetic studies of the distribution of genotypes and frequencies of polymorphic variants of thegenes GSTT1, GSTM1, GSTP1 were performed in children living under long-term intake of 137Cs by food chains. It wasfound that in children with BA the tendency to frequency of the deletion variant of the GSTT1 and GSTM1 genes incomparison with children without bronchial and pulmonary pathology was increased. The study of distributing theGSTP1 A313G gene polymorphic variants revealed in children with BA a significant increase in the frequency of AG-genotype, compared with the data of reference group. Adverse factors that increase the risk of developing bron-choobstructive disorders and the probability of their implementation in the form of bronchial asthma in children -residents of RCA have been identified. It is established that among them the leading role is played by hereditarypredisposition to this disease. On the part of the child, such negative factors were unfavorable conditions of fetaldevelopment, the presence of signs of exudative-catarrhal diathesis, manifestations of allergies and frequent respi-ratory diseases from the first months of life. It was found that the risk of developing BA was significantly increasedin children with the GSTT1 and GSTM1 gene deletion genotypes; an increased risk of developing BA in children witha combination of the GSTP1 A313G gene polymorphism with deletion polymorphism of the GSTT1 or GSTM1 gene wasdetermined. Сonclusion. Оne of the leading mechanisms, due to which there is a realization of hereditary predisposition tobronchial asthma in children living under constant intake of radionuclides with a long half-life, is the polymorphismof certain glutathione-S-transferase genes, namely, GSTT1, GSTM1 and A313G gene deletion polymorphism and GSTP1gene polymorphism.

Effects of GSTT1 and GSTM1 polymorphisms in glutathione levels and breast cancer development in Brazilian patients.

Polymorphisms in the glutathione transferase enzymes (GSTs) genes have been associated with susceptibility to develop breast cancer (BC), but few are known regarding its role on this disease prognosis and impact on antioxidant status. This study evaluated the polymorphisms of GSTM1 and GSTT1 genes and their relationship with BC susceptibility and prognostic, as well as its impact on plasma reduced glutathione (GSH) levels. The present study included 121 women with invasive ductal BC and 151 healthy controls. Polymorphisms analyses were performed using the polymerase chain reaction (PCR) technique and GSH levels were measured with the Ellman's reagent. GSTT1 (OR 1.29; p = 0.39) and GSTM1 (OR 1.03; p = 0.91) polymorphisms did not show any association with BC susceptibility. The mean concentration values in nmol/L of GSH were 20.37 ± 5.82 for patients with null genotypes for both genes, 19.75 ± 3.47 for null GSTT1, 17.22 ± 1.35 for active GSTT1, 18.82 ± 1.96 for absent GSTM1, and 16.59 ± 1.66 for active GSTM1, but no significance was found. Therefore, it can be concluded that the behavior of these polymorphisms concerning BC might be not only related to the absence of enzymatic expression but may also be related to the body's response with its antioxidant mechanisms and it should be further studied.

Search for association of deletion polymorphisms of glutathione-S-transferase GSTM1 and GSTT1 genes with risk of lung cancer in the Yakut population

Search for association of deletion polymorphisms of glutathione-S-transferase GSTM1 and GSTT1 genes with risk of lung cancer in the Yakut population

Deletion polymorphism of GSTT1 gene and lipid peroxidation hyperactivation in menopausal insomnia

A comparative analysis of the parameters of lipid peroxidation - antioxidant defense system in menopausal women with- and without insomnia, depending on the GSTT1 polymorphism. The study included 181 menopausal Caucasian women (ethnic group - Russians), who according to the results of the clinical-anamnestic examinations were divided into insomnia group (n=120, age 53.68±4.61 years, body mass index 26.47±3.73 kg/m2) and control group (n=61, age 52.64±4.91 years, body mass index 27.69±3.11 kg/m2). The insomnia group was formed according to the clinical guidelines for the diagnosis and treatment of chronic insomnia in adults, and scores of the Insomnia Severity Index. The study of the GSTT1 gene polymorphism was carried out using polymerase chain reaction. The lipid peroxidation - antioxidant system parameters were determined by spectrofluorophotometric methods. In the insomnia group, carriers of the normal GSTT1 genotype had higher diene conjugates with lower glutathione peroxidase activity as compared to controls. When comparing groups of women with the deletion in GSTT1, an increase in the content of substrates and lipid peroxidation products was observed at all stages of lipid peroxidation, oxidized glutathione, glutathione S-transferase activity with a decrease in the content of reduced glutathione and retinol in the insomnia group as compared to controls. In the insomnia group, carriers of the deletion genotype had a higher content of ketodienes/conjugated trienes and active products of thiobarbituric acid, a lower content of retinol and α-tocopherol as compared to the patients with normal GSTT1 genotype. Conclusions. Insomnia in the menopausal women is accompanied with the intensification of lipid peroxidation only in the carriers of the GSTT1 deletion genotype.

Effects of GSTT1 Genotype on the Detoxification of 1,3-Butadiene Derived Diepoxide and Formation of Promutagenic DNA-DNA Cross-Links in Human Hapmap Cell Lines.

Smoking is a leading cause of lung cancer, accounting for 81% of lung cancer cases. Tobacco smoke contains over 5000 compounds, of which more than 70 have been classified as human carcinogens. Of the many tobacco smoke constituents, 1,3-butadiene (BD) has a high cancer risk index due to its tumorigenic potency and its abundance in cigarette smoke. The carcinogenicity of BD has been attributed to the formation of several epoxide metabolites, of which 1,2,3,4-diepoxybutane (DEB) is the most toxic and mutagenic. DEB is formed by two oxidation reactions carried out by cytochrome P450 monooxygenases, mainly CYP2E1. Glutathione-S-transferase theta 1 (GSTT1) facilitates the conjugation of DEB to glutathione as the first step of its detoxification and subsequent elimination via the mercapturic acid pathway. Human biomonitoring studies have revealed a strong association between GSTT1 copy number and urinary concentrations of BD-mercapturic acids, suggesting that it plays an important role in the metabolism of BD. To determine the extent that GSTT1 genotype affects the susceptibility of individuals to the toxic and genotoxic properties of DEB, GSTT1 negative and GSTT1 positive HapMap lymphoblastoid cell lines were treated with DEB, and the extent of apoptosis and micronuclei (MN) formation was assessed. These toxicological end points were compared to the formation of DEB-GSH conjugates and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) DNA-DNA cross-links. GSTT1 negative cell lines were more sensitive to DEB-induced apoptosis as compared to GSTT1 positive cell lines. Consistent with the protective effect of GSH conjugation against DEB-derived apoptosis, GSTT1 positive cell lines formed significantly more DEB-GSH conjugate than GSTT1 negative cell lines. However, GSTT1 genotype did not affect formation of MN or bis-N7G-BD cross-links. These results indicate that GSTT1 genotype significantly influences BD metabolism and acute toxicity.

Epigenetic study of global gene methylation in PON1, XRCC1 and GSTs different genotypes in rural and urban pesticide exposed workers.

Background Epigenetic represents a study of occurred heritable gene expression changes without changing in the DNA sequence. It includes DNA methylation and miRNA expression that attract increasing attention as potential links between the genetic and environmental determinants of health and disease. Pesticide exposure is associated with adverse health effects and DNA methylation due to oxidative stress induced following its exposure. This study aimed to define the association of genetic polymorphisms of XRCC1, PON1, GSTP1 and GST genes with global genes DNA methylation in urban and rural occupationally pesticides exposed workers. Methods This study included 100 pesticides exposed workers; 50 rural sprayers (RE) and 50 urban researchers (UE). Controls included equal numbers. DNA methylation of global genes was evaluated by pyrosequencing assay. XRCC1, PON1 and GSTP1 genotyping were assessed by PCR-RFLP, and GST M1 and T1 were performed by PCR. Results The results of this study revealed that most genotypes in XRCC1, PON1, GSTP1 and GST genes were associated with LINE-1 hypomethylation among UE group. However, heterozygote genotypes (Gln-Arg and Ile-Val) in XRCC1 and GSTP1 genes, respectively, were associated with LINE-1 hypermethylation among UE compared with other corresponding genotypes. Only GSTT1 polymorphism recorded a significant change in percent methylation of Alu elements among urban and rural groups. Conclusion Urbanization could play an additional risk for epigenetic changes associated with pesticide exposure, and that could be attributed to the quality of life including their dietary habits, working and living in closed areas, and their exposure to extra pollutions emitted from urbanization sources.

GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel-Based Chemotherapy in Ovarian Cancer.

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014–2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion of GSTM1 and GSTT1 genes. GSTP1 (c.313A>G/rs1695) and ABCB1 (c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real‐time PCR. Subjects with the GSTP1 c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.69, P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12–0.64, P < 0.01; OR 0.18, 95% CI 0.03–0.85, P = 0.03, either dominant or recessive model), respectively. The GSTP1 c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13–0.90, P = 0.03). The ABCB1 c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03–0.82, P = 0.03), whereas ABCB1 c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08–121.01, P = 0.03) in recessive model (CC + CT vs. TT). This study suggests that GSTP1 c.313A>G, ABCB1 c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.

Identification of glutathione-S-transferase gene polymorphisms in type 2 diabetes mellitus patients attending Abdullahi Wase Specialist Hospital, Kano State Nigeria

Glutathione-S-transferases (GSTs) are a family of antioxidant enzymes that include several classes with various polymorphisms. This work was aimed at investigating the association between the polymorphisms of the GSTT1 gene and type 2 diabetes mellitus (T2DM). The frequency of GSTT1 genotypes in T2DM patients and non-diabetic controls were studied. A total of 30 diagnosed cases of type 2 diabetes mellitus were selected from the diabetes clinic section of Abdullahi Wase Specialist Hospital, Kano Nigeria. A total of 30 non-diabetic individuals were also selected as control from the outpatient department (OPD) section of the hospital. All the subjects were assessed for fasting blood sugar (FBS), body mass index (BMI), Systolic and Diastolic Blood Pressures (SBP and DBP) and the genotypes of GSTT1 were determined using multiplex polymerase chain reaction (mPCR) techniques. FBS and BMI were significantly high (P<0.05) in diabetics (225.58±83.58mg/dL and 27.53±3.99kg/m2 respectively) as compared to the non-diabetic controls (90.85±14.87mg/dL and 21.46±4.36kg/m2 respectively). There were no significant differences (P<0.05) for SBP and DBP in the diabetics (125.73±20.72mmHg and 85.83±13.65mmHg respectively) as compared to the non-diabetic controls (117.33±3.04mmHg and 79.90±10.05mmHg respectively). This implies that the body weight of the diabetic patients is increased being a risk factor in diabetes mellitus. Furthermore, the GSST1 positive polymorphism was present in 95% of the samples analyzed (i.e. diabetics and controls). There was no presence of the deletion polymorphism in the two groups. This implies that there was no association of GSTT1 polymorphisms with T2DM in the studied population; Even though GSTT1 is associated with T2DM in other populations. Other polymorphisms of GST should be studied to ascertain their roles in the pathogenesis of T2DM in this population.

145 President Oral Presentation Pick: Prenatal stress increases skeletal muscle mitochondrial volume density and function in yearling Brahman calves

Abstract We previously determined that prenatal stress (PNS) differentially affected methylation of DNA from leukocytes of 28-d-old calves. Specifically, COX14 (cytochrome c oxidase (COX) assembly factor) and CKMT1B (mitochondrial creatine kinase U-type) were hypomethylated and COA5 (COX assembly factor 5), COX5A (COX subunit 5A), NRF1 (nuclear respiratory factor 1), and GSST1 (glutathione S-transferase theta-1) were hypermethylated in PNS compared to non-PNS calves (P ≤ 0.05). Our current objective was to test the hypothesis that PNS exhibit impaired mitochondrial function and greater oxidative stress than non-PNS calves. Blood and longissimus dorsi muscle samples were collected from yearling Brahman calves whose mothers were stressed by 2 h transportation at 60, 80, 100, 120, and 140 days of gestation (PNS; 8 bulls, 6 heifers) and non-PNS calves (4 bulls, 6 heifers). Serum was evaluated for the stress hormone, cortisol, and muscle damage marker, creatine kinase; muscle was analyzed for mitochondrial volume density and function by citrate synthase (CS) and COX activities, respectively, concentration of malondialdehyde, a lipid peroxidation marker, and activity of the antioxidant, superoxide dismutase (SOD). Data were analyzed using mixed linear models with treatment and sex as fixed effects. Serum cortisol was numerically higher in PNS than non-PNS calves but was not statistically different. Muscle CS and COX activities relative to protein were greater in PNS than non-PNS calves (P ≤ 0.03), but COX relative to CS activity was similar between groups. Activity of COX was greater in bulls than heifers (P = 0.03), but no other measure was affected by sex. All other measures were unaffected by PNS. Prenatal stress did not affect markers of muscle damage and oxidative stress in yearling Brahman calves at rest but mitochondrial volume density and function were greater in PNS calves. Acute stressors induce oxidative stress, so implications of differences in mitochondria in PNS calves following a stressor should be investigated.

Визначення предикторів ризику затримки статокінетичного розвитку і поліморфізму генів GSTP1, GSTT1, GSTM1, ACE, AGT2R1 та ENOS у передчасно народжених дітей з дуже і надзвичайно малою масою тіла при народженні

World statistics and scientific research show that premature birth of children is accompanied by a high risk of not only somatic, but also neurological pathology and mental disorders development. Therefore, the clinical prognostic model development for the research of delayed infant statokinetic development, which was born prematurely, may be the basis for creating a preventive program of early intervention. Purpose — to determine the clinical and genetic delayed statokinetic development formation determinants of children born with a body weight less than 1500 g; to develop an algorithm for early prediction of adverse effects. Materials and methods. A cohort prospective study was conducted, which included 155 children with very low and extremely low body weight. Their statokinetic development at 6, 12, 18, 24 and 36 months of adjusted age was studied and the determinants were established. Genetic methods included studies of the GSTP1, GSTT1, GSTM1, ACE, AGT2R1, and eNOS genes polymorphism. Results. It was defined that at 24 months of adjusted age 19% have delayed statokinetic development, at 36 months — 16% of examined children have very low and extremely low body weight. Important predictors that contribute a delayed statokinetic development were severe intraventricular hemorrhages, anemia in the second year of life, significant delay in physical development at 6 months and socio-economic status of the family. The greatest delay in the motor sphere was found in children with a dominant genetic model (GG+AG vs. AA) of the GSTP1 gene. Conclusions. The developed model for predicting motor developmental delay at an early age has a high specificity (92.44%) and moderate sensitivity (53.33%), which indicates the possibility of its use for forecasting and personalized method of treatment. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: prediction, statokinetic development, very low body weight, extremely low body weight, premature babies, premature infants.

Polymorphisms of the GSTT1 and GSTM1 genes in polycystic ovary syndrome.

This study aimed to investigate the deletion polymorphisms of the genes of the glutathione S-transferase family GSTT1 and GSTM1 in patients with Polycystic Ovarian Syndrome (PCOS), comparing them with a control population. Blood was collected from 219 women (110 with PCOS and 109 controls) and genomic DNA was extracted. For the analysis of polymorphisms, the technique used was multiplex PCR. In the statistical analysis, the chi-square test and multiple logistic regression were used. There is no association between the GSTM1 null and GSTT1 null genotypes with PCOS when analyzed separately (P = 0.616 and P = 0.188). The analysis of the combined genotypes showed differences between the groups (P < 0.05), evidencing that the genotypic combination GSTT1 positive and GSTM1 negative is more frequent among patients. In the multivariate analysis, smoking was more frequent in the control group (OR = 0.22; 95% CI - 0.87-0.57; P = 0.002) while the presence of a family history of PCOS (OR = 2, 96; 95% CI - 1.54-5.68; P = 0.001) was more frequent in women with PCOS. In the studied sample, the deletion polymorphisms of the GSTT1 and GSTM1 genes isolated are not associated with PCOS, but in combination, they may be implicated in the etiology of the condition.

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases.

Glutathione S-transferases (GSTs) are metabolic enzymes responsible for the elimination of endogenous or exogenous electrophilic compounds by glutathione (GSH) conjugation. In addition, GSTs are regulators of mitogen-activated protein kinases (MAPKs) involved in apoptotic pathways. Overexpression of GSTs is correlated with decreased therapeutic efficacy among patients undergoing chemotherapy with electrophilic alkylating agents. Using GST inhibitors may be a potential solution to reverse this tendency and augment treatment potency. Achieving this goal requires the discovery of such compounds, with an accurate, quick, and easy enzyme assay. A spectrophotometric protocol using 1-chloro-2,4-dinitrobenzene (CDNB) as the substrate is the most employed method in the literature. However, already described GST inhibition experiments do not provide a protocol detailing each stage of an optimal inhibition assay, such as the measurement of the Michaelis-Menten constant (Km) for CDNB or indication of the employed enzyme concentration, crucial parameters to assess the inhibition potency of a tested compound. Hence, with this protocol, we describe each step of an optimized spectrophotometric GST enzyme assay, to screen libraries of potential inhibitors. We explain the calculation of both the half-maximal inhibitory concentration (IC50) and the constant of inhibition (Ki)-two characteristics used to measure the potency of an enzyme inhibitor. The method described can be implemented using a pool of GSTs extracted from cells or pure recombinant human GSTs, namely GST alpha 1 (GSTA1), GST mu 1 (GSTM1) or GST pi 1 (GSTP1). However, this protocol cannot be applied to GST theta 1 (GSTT1), as CDNB is not a substrate for this isoform. This method was used to test the inhibition potency of curcumin using GSTs from equine liver. Curcumin is a molecule exhibiting anti-cancer properties and showed affinity towards GST isoforms after in silico docking predictions. We demonstrated that curcumin is a potent competitive GST inhibitor, with an IC50 of 31.6 ± 3.6 µM and a Ki of 23.2 ± 3.2 µM. Curcumin has potential to be combined with electrophilic chemotherapy medication to improve its efficacy.

Exposure to traffic-related particle matter and effects on lung function and potential interactions in a cross-sectional analysis of a cohort study in west Sweden

ObjectivesTo investigate the long-term effects of source-specific particle matter (PM) on lung function, effects of Surfactant Protein A (SP-A) and glutathione S-transferase (GST) genes GSTP1 and GSTT1 gene variants and...

Association of Glutathione S-Transferase theta 1 and mu 1 Genes Polymorphisms with the Susceptibility of Myocardial Infarction in Bangladesh.

Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Oxidative stress plays a vital role in the pathogenesis of atherosclerosis leading to myocardial infarction and Glutathione S-transferases (GSTs) act as detoxifying enzymes to reduce oxidative stress. The aim of the present study was to investigate the associations of the GST (T1 & M1) gene polymorphism with the susceptibility of myocardial infarction in the Bangladeshi population. A case-control study on 100 cardiac patients with MI and 150 control subjects was conducted. The genotyping of GST (T1 & M1) gene was done using conventional Polymerase Chain Reaction. The percentage of GSTM1 genotypes was significantly (p< 0.01) lower in patients compared to control subjects while the GSTT1 genotypes were not significantly different between the study subjects. The individual with GSTM1 null allele was at 2.5-fold increased risk {odds ratio (OR)= 2.5; 95 % confidence interval (95 % CI)= 1.4 to 4.3; p< 0.01} of experiencing MI while individual with either GSTM1 or GSTT1 genotypes was at lower risk. In the case of GST M1 and GST T1 combined genotype, patients having both null genotypes for GST M1 and GST T1 gene showed significantly (p< 0.01) higher risk of experiencing MI when compared to control subjects (OR= 3.5; 95% CI= 1.7-7.2; p< 0.001). Thus our recent study suggested that GSTM1 alone and GSTM1 and T1 in combination augments the risk of MI in Bangladeshi population.

In silico and in vitro investigations on the protein–protein interactions of glutathione S-transferases with mitogen-activated protein kinase 8 and apoptosis signal-regulating kinase 1

Cytosolic glutathione S-transferase (GST) enzymes participate in several cellular processes in addition to facilitating glutathione conjugation reactions that eliminate endogenous and exogenous toxic compounds, especially electrophiles. GSTs are thought to interact with various kinases, resulting in the modulation of apoptotic processes and cellular proliferation. The present research used a combination of in silico and in vitro studies to investigate protein–protein interactions between the seven most abundant cytosolic GSTs—GST alpha-1 (GST-A1), GST alpha-2 (GST-A2), GST mu-1 (GST-M1), GST mu-2 (GST-M2), GST mu-5 (GST-M5), GST theta-1 (GST-T1) and GST pi-1 (GST-P1)—and Mitogen-activated protein kinase 8 (MAPK8) and Apoptosis signal-regulating kinase 1 (ASK1). MAPK8 and ASK1 were chosen as this study’s protein interaction partners because of their predominant role in electrophile or cytokine-induced stress-mediated apoptosis, inflammation and fibrosis. The highest degree of sequence homology or sequence similarity was observed in two GST subgroups: the GST-A1, GST-A2 and GST-P1 isoforms constituted subgroup1; the GST-M1, GST-M2 and GST-M5 isoforms constituted subgroup 2. The GST-T1 isoform diverged from these isoforms. In silico investigations revealed that GST-M1 showed a significantly higher binding affinity to MAPK8, and its complex was more structurally stable than the other isoforms, in the order GST-M1 > GST-M5 > GST-P1 > GST-A2 > GST-A1 > GST-M2 > GST-T1. Similarly, GST-A1, GST-P1 and GST-T1 actively interacted with ASK1, and their structural stability was also better, in the order GST-T1 > GST-A1 > GST-P1 > GST-A2 > GST-M5 > GST-M1 > GST-M2. To validate in silico results, we performed in vitro crosslinking and mass spectroscopy experiments. Results indicated that GST-M1 interacted with GST-T1 to form heterodimers and confirmed the predicted interaction between GST-M1 and MAPK8. Communicated by Ramaswamy H. Sarma

Two resveratrol analogs, pinosylvin and 4,4′-dihydroxystilbene, improve oligoasthenospermia in a mouse model by attenuating oxidative stress via the Nrf2-ARE pathway

Two synthesized resveratrol analogs from our laboratory, namely pinosylvin (3,5-dihydroxy-trans-stilbene, PIN) and 4,4′-dihydroxystilbene (DHS), have been carefully evaluated for treatment of oligoasthenospermia. Recent studies have demonstrated that PIN and DHS improved sperm quality in the mouse. However, the mechanism of action of PIN and DHS on oligoasthenospermia remains unknown. Herein, we investigated the mechanistic basis for improvements in sperm parameters by PIN and DHS in a mouse model of oligoasthenospermia induced by treatment with busulfan (BUS) at 6 mg/kg b.w.. Two weeks following busulfan treatment, mice were administered different concentrations of PIN or DHS daily for 2 consecutive weeks. Thereafter, epididymal sperm concentration and motility were determined, and histopathology of the testes was performed. Serum hormone levels including testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured using corresponding specific enzyme-linked immunosorbent assay (ELISA) kits. Testicular mRNA expression profiles were determined by RNA sequencing analysis. These findings were validated by quantitative real-time PCR, western blotting and ELISA. Both PIN and DHS improved the epididymal sperm concentration and motility, enhanced testosterone levels, and promoted testicular morphological recovery following BUS treatment. PIN treatment was found to significantly reduce oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE)-dependent antioxidant, glutathione peroxidase 3. DHS treatment significantly reduced oxidative stress via the Nrf2-ARE-dependent antioxidants glutathione S-transferase theta 2 and glutathione S-transferase omega 2. In summary, PIN and DHS ameliorated oligoasthenospermia in this mouse model by attenuating oxidative stress via the Nrf2-ARE pathway.

Association of CYP1A1, GSTM1 and GSTT1 gene polymorphisms with risk of prostate cancer in Algerian population

BackgroundProstate cancer is the most common cancer in the world, and its etiology involves the interaction of genetic and environmental factors. Interindividual differences observed in the metabolism of xenobiotics may be due to polymorphisms of genes encoding the detoxification enzymes. This genetic variability seems to be associated with differences in susceptibility to certain types of cancers, including prostate cancer. Our study has been made in order to investigate a possible genetic predisposition to prostate cancer in an Algerian population, through the analysis of genetic polymorphisms of three enzymes metabolizing xenobiotics namely cytochrome P450 (CYP) 1A1, glutathione S-transferase mu 1 (GSTM1) and GST theta 1 (GSTT1).MethodsThe current case–control study included 101 prostate cancer patients and 101 healthy controls. Genotyping of CYP1A1 T3801C polymorphisms and GSTM1/GSTT-null was made, respectively, by PCR-RFLP and multiplex PCR.ResultsNo significantly positive associations were found for the CYP1A1 T3801C [p = 0.71, OR = 1.23 (0.56–2.72)] and GSTM1-null [p = 0.26, OR = 1.37 (0.76–2.4)] polymorphisms and prostate cancer susceptibility. However, we detect a highly significant association between GSTT1-null genotype [p = 0.03, OR = 2.03 (1.06–3.99)], GSTM1/GSTT1-double null genotype [p = 0.027, OR = 2.6; CI (1.07–6.5)] and prostate cancer risk. Furthermore, no statistically significant differences between the studied polymorphisms and tumor parameters (the Gleason score and clinical stages of aggressiveness) at diagnosis of PCa.ConclusionsThe risk of developing prostate cancer in Algeria does not appear to be associated with CYP1A1 T3801C genotypes and GSTM1-null, but GSTT1-null and GSTM1/GSTT1-double null genotypes increased the risk of prostate cancer.