Glutathione S-transferase Polymorphisms Research Articles

Human variability in glutathione-S-transferase activities, tissue distribution and major polymorphic variants: Meta-analysis and implication for chemical risk assessment

The input into the QIVIVE and Physiologically-Based kinetic and dynamic models of drug metabolising enzymes performance and their inter-individual differences significantly improve the modelling performance, supporting the development and integration of alternative approaches to animal testing. Bayesian meta-analyses allow generating and integrating statistical distributions with human in vitro metabolism data for quantitative in vitro-in vivo extrapolation. Such data are lacking on glutathione-S-transferases (GSTs). This paper reports for the first time results on the human variability of GST activities in healthy individuals, their tissue localisation and the frequencies of their major polymorphic variants by means of extensive literature search, data collection, data base creation and meta-analysis.A limited number of papers focussed on in vivo GST inter-individual differences in humans. Ex-vivo total GST activity without discriminating amongst isozymes is generally reported, resulting in a high inter-individual variability.The highest levels of cytosolic GSTs in humans are measured in the kidney, liver, adrenal glands and blood. The frequencies of GST polymorphisms for cytosolic isozymes in populations of different geographical ancestry were also presented. Bayesian meta-analyses to derive GST-related uncertainty factors provided uncertain estimates, due to the limited database.Considering the relevance of GST activities and their pivotal role in cellular adaptive response mechanisms to chemical stressors, further studies are needed to identify GST probe substrates for specific isozymes and quantify inter-individual differences.

Evaluation of glutathione S-transferase polymorphism in Iranian patients with type 2 diabetic microangiopathy

BackgroundOverproduction of reactive oxygen species as a result of hyperglycemia in diabetes mellitus leads to microvascular complications. Glutathione S-transferases play important detoxifying roles with antioxidant potentials. This study aimed to assess whether the glutathione S-transferase M1 and T1 genotypes were associated with type 2 diabetes mellitus microangiopathic complications in the Iranian population.ResultsIn this case-control study, the frequencies of null GSTM1 and GSTT1 genotypes were 4/72 (5.56%) and 12/72 (16.67%) respectively, in uncomplicated DM group. The frequencies of null GSTM1 and GSTT1 genotype in complicated DM group were 16/134 (11.94%) and 37/134 (27.61%), respectively. The proportion of GSTM1 null genotypes was higher in diabetic nephropathy compared to non-nephropathy (19.3% vs. 6.04 %, P = 0.006). At GSTT1 locus, patients with diabetic peripheral neuropathy had a higher frequency of deletion compared to those of without neuropathy (30.39% vs. 23.49%) (P = 0.02).ConclusionSelective polymorphisms encoding GSTM1 and GSTT1genes may prove useful as genetic markers to recognize individuals with an increased trend in developing diabetic nephropathy and neuropathy, respectively. This will help better identify individuals at higher risk toward microvascular complications of type 2 diabetes due to genetic susceptibility.

Genetic Polymorphism of Glutathione S-transferase and Cervical Cancer Susceptibility in Northeastern Thailand

Background: Exposure to certain carcinogens together with host genetic predisposition likely has an influence on cervical carcinogenesis. Objective: Our aim was to evaluate synergistic effects of glutathione S-transferase (GST) polymorphisms and risk behaviors (i.e., smoking and contraceptive use) on squamous cell cervical cancer (SCCA) development in northeastern Thailand. Methods: Subjects were 198 (SCCA) patients and 198 age-matched healthy controls. Multiplex PCR and PCR-RFLP were used to determine GSTT1 and GSTA1 gene polymorphism, respectively. Results: Interaction between the four polymorphic loci of GSTs (GSTM1, GSTT1, GSTP1 and GSTA1) and increased risk for cervical cancer was not observed. The three genotypes of GSTM1 consistently showed significant risks of smoking with a lower OR for the Null individuals (1.741) at around one -fourth of wild type homozygous individuals (8.000). The effects of GST polymorphisms on cervical cancer risk under the use of hormonal contraceptives apparently did not occur. Conclusions: The predisposition of smoking risk is related to the GST genotype. It is suggested that knowing one’s own genotype data will contribute to the prevention of SCCA by controlling risk habits.

Glutathione S-transferase Polymorphisms in Head and Neck Squamous Cell Carcinoma Treated with Chemotherapy and/or Radiotherapy.

Background/Aim:The Glutathione S-transferases (GSTs) are important carcinogen-metabolizing enzymes. Polymorphisms involved in these enzymes can modulate the development and treatment of head and neck cancer. To investigate the association of GSTs polymorphisms with head and neck cancer and risk factors, clinical-pathological features, and survival time of the patients treated with chemotherapy and/or radiotherapy. Methods:The GST gene polymorphisms were evaluated in 197 cases and 514 controls by PCR-RFLP-Polymerase Chain Reaction Restriction Fragment Length Polymorphism. Results:The GSTP-313 was associated with a decreased risk for HNSCC (p=0.050). The GSTP1 haplotype analysis revealed a higher frequency of the AC and AT haplotypes in the case group than in the control group (p=0.013 and p=0.019, respectively), and the opposite for G-C haplotype (p = 0.015). Yet, the different combinations between the genotypes were associated with an increased risk of cancer. The study showed no association between the polymorphisms and primary tumor site, clinical-pathological characteristics, treatment (chemotherapy and/or radiotherapy) and survival time of the patients. Conclusion:The GST polymorphisms combination showed an increased risk for carcinogenesis, and studies with larger casuistry can contribute to the clarification of the role in individual patient differences for the response to chemotherapy and/or radiotherapy and identify biomarkers of susceptibility.

Персонифицированная гепатопротекция больных механической желтухой доброкачественного происхождения

Целью исследования явилось изучение эффективности ремаксола у больных механической желтухой неопухолевого происхождения в зависимости от генетических полиморфизмов генов антиоксидантных ферментов. Обследованы 78 пациентов, оперированных по поводу механической желтухи (МЖ) неопухолевого происхождения. Выделены 2 группы: первая (n = 39) — пациентам в раннем послеоперационном периоде проводилось базисное лечение и вторая (n = 39) — в терапию включены и инфузии ремаксола (400 мл). В динамике проведены лабораторные и биохимические исследования: оценивали функциональные показатели печени, интенсивность перекисного окисления мембранных липидов, активность фосфолипазы A2, выраженность гипоксии и др. Также проведен молекулярно-генетический тест полиморфизмов генов супероксиддисмутазы (SOD2, C47T), каталазы (CAT, -262C/T) и глутатион-S-трансферазы (GSTP1, C114T), выделенных из венозной крови при помощи модернизированного метода Laura-Lee Boodram. Анализ генетических локусов произведен с помощью наборов DNA-Extran-1 при использовании полимеразной цепной реакции в реальном времени (CFX96 Touch™ Real-Time PCR Detection System, США). Установлено, что применение ремаксола на раннем периоде развития механической желтухи способствовало ингибированию липопереокисления, фосфолипазной активности, восстановлению функционально-метаболического состояния печени. Результаты генетического исследования показали, что полиморфизмы SOD2, каталазы и GSTP1 играют важную роль не только в прогрессировании патологии, но и эффективности терапии. Оказалось, что в группе пациентов с высокой частотой встречаемости редких генетических маркеров (C/T и T/T составили 28,2 и 33,3 %) полиморфизмов генов антиоксидантных ферментов выраженность оксидативного стресса выше. Об этом свидетельствует повышение содержания диеновых конъюгатов (ДК) на весь период исследования на 24,5 – 33,1 % (p = 0,01), малонового диальдегида (МДА) — на 22,6 – 32,6 % (p = 0,01) и значения индекса гипоксии (ИГ) — на 12,6 – 14,9 % (p = 0,01), активирование фосфолипазы (ФЛ) A2 на 23,6 – 35,6 % (p = 0,01), и ингибирование интенсификации антиоксидантной супероксиддисмутазы (СОД) на 19,8 – 26,5 % (p = 0,01). При этом эффективность ремаксола проявляется в большей степени (интенсивность ДК, МДА и ИГ уменьшалась на 29,6 – 35,6, 28,4 – 38,5 и 22,2 – 26,7 % (p = 0,02), активность ФЛ A2 падала на 39,6 – 42,5 % (p = 0,01), а СОД возрастала на 18,8 – 23,7 % (p = 0,01). Таким образом, результаты исследования являются основанием для своевременного проведения тестов на определение частоты встречаемости патологических генотипов полиморфизмов генов антиоксидантной ферментной системы при МЖ и установление их сопряженности с гомеостатическими показателями, что позволит персонифицировано прогнозировать течение патологии и оценить схему лечения больных механической желтухой.

Effects of glutathione S-transferase M1 and T1 deletions on Parkinson's disease risk among a North African population.

In this study, the effects of glutathione S-transferase polymorphisms Mu1 (GSTM1) and glutathione S-transferase polymorphisms Theta1 (GSTT1) on Parkinson's disease (PD) risk factor were evaluated in a Tunisian population. These polymorphisms were analyzed in 229 healthy Tunisian subjects and 64 Tunisian patients with PD, using a polymerase chain reaction (PCR). Statistical analysis was performed using SPSS 18.0. The relative associations between the GST genotypes and PD were assessed by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). The study results demonstrated that the individuals with GSTM1 [OR=3.93, 95% CI: 1.98-7.92, P=10-6] and GSTT1 [OR=5.45, 95% CI: 2.90-10.30, p=10-6] were statistically associated with the risk of PD. A significant association was also found between the individuals with both GSTM1/T1 null genotypes and PD risk [OR=22.10, 95% CI: 6.99-73.75, P=10-6]. These genotyping findings suggest that the absence of both GSTM1 and GSTT1 activity could be a contributory factor for the development of PD.

GC-MS Based Metabolic Profiling of Parkinson's Disease with Glutathione S-transferase M1 and T1 Polymorphism in Tunisian Patients.

Parkinson's disease (PD) is the second most common neurodegenerative disease. It is a multifactorial disorder (caused by aging, environmental, and genetic factors). Metabolomics can help explore the biomarker profiles for aging. Recent studies showed an association between the glutathione S-transferases (GSTs) polymorphisms and PD risk. The purpose of this study was to evaluate the association of this genetic polymorphism and the metabolomic profile in PD Tunisian patients, in order to identify effective biomarkers in the genetic differentiation. In this study, the metabolomic profile changes related to GSTs polymorphism were searched in 54 Tunisian PD patients treated with L-dopa, using a gas chromatography-mass spectrometry (GC-MS) technique. The study results showed that mannose, methyl stearate, and three other unknown metabolites, increased in patients with GSTM1 positive genotype, while glycolic acid, porphine, monomethyl phosphate, fumaric acid, and three other unknown metabolites decreased in patients with GSTM1 positive genotype. Subsequently, the levels of glycolic acid, erythronic acid, lactic acid, citric acid, fructose, stearic acid, 2-amino-2-methyl-1,3-propanediol and three other unknown metabolites increased in patients with GSTM1 positive genotype, while the levels of proline, valine and two unknown metabolites decreased with GSTT1 positive genotype. All these altered metabolites are related to energy metabolism and it can be concluded that GSTs polymorphism based the shifting in energy metabolism and led to oxidative stress.

Intake of total cruciferous vegetable and its contents of glucosinolates and isothiocyanates, glutathione S-transferases polymorphisms and breast cancer risk: a case-control study in China.

Cruciferous vegetables contain high levels of glucosinolates (GSL) and isothiocyanates (ITC). ITC are known to induce glutathione S-transferases (GST) and thus exert their anticarcinogenic effects. This study explored the combined effects of cruciferous vegetable, GSL and ITC intake and GST polymorphisms on breast cancer risk. A total of 737 breast cancer cases and 756 controls were recruited into this case-control study. OR and 95 % CI were assessed by multivariable logistic regression. Higher cruciferous vegetable, GSL and ITC intakes were inversely associated with breast cancer risk, with adjusted OR of 0·48 (95 % CI 0·35, 0·65), 0·54 (95 % CI 0·40, 0·74) and 0·62 (95 % CI 0·45, 0·84), respectively. Compared with women carrying the GSTP1 rs1695 wild AA genotype and high cruciferous vegetable, GSL or ITC intake, carriers of the AA genotype with low cruciferous vegetable, GSL and ITC intake had greater risk of breast cancer, with adjusted OR of 1·43 (95 % CI 1·01, 1·87), 1·34 (95 % CI 1·02, 1·75) and 1·37 (95 % CI 1·05, 1·80), respectively. Persons with the GSTM1-null genotype and lower intake of cruciferous vegetables, GSL and ITC had higher risk of breast cancer than those with the GSTM1-present genotype and higher intake, with OR of 1·42 (95 % CI 1·04, 1·95), 1·43 (95 % CI 1·05, 1·96) and 1·45 (95 % CI 1·06, 1·98), respectively. Among women possessing the GSTT1-present genotype, low intake of cruciferous vegetables, GSL or ITC was associated with higher risk of breast cancer. But these interactions were non-significant. This study indicated that there were no significant interactions between cruciferous vegetable, GSL or ITC intake and GST polymorphisms on breast cancer risk.

GSTM1-null allele predicts rapid disease progression in nondialysis patients and mortality among South Indian ESRD patients.

Chronic kidney disease (CKD) is one of the main causes of early death in humans worldwide. Glutathione S-Transferases (GSTs) are involved in a series of xenobiotics metabolism and free radical scavenging. The previous studies elucidated the interlink between GST variants and to the development of various diseases. The present case-control study performed to ascertain whether GST polymorphisms are associated with the incidence and advancement of CKD. From the Southern part of India, a total of 392 CKD patients (nondialysis, ND; n = 170, end-stage renal disease, ESRD; n = 222) and 202 healthy individuals were enrolled. Patients were followed-up for 70months. Serum biochemical parameters were recorded, and the extraction of DNA was done from the patient's blood samples. To genotype study participants, multiplex PCR for GSTM1/T1 was performed. Statistical analysis was carried out to analyze the relationship between gene frequency and sonographic grading, as well as biochemical parameters for disease development. The GSTM1-null genotype showed threefold increased risk (OR = 2.9304; 95% CI 1.8959 to 4.5296; P < 0.0001) to CKD development and twofold increased risk (OR = 1.8379; 95% CI 1.1937 to 2.8299; P = 0.0057) to ESRD progression. During the mean follow-up of 41months study, multivariate Cox regression analysis revealed that GSTM1-null genotype has 4 times increased the risk for all-cause rapid disease progression to ESRD among ND patients and 3.85-fold increased risk for death among ESRD patients. Survival analysis revealed that patients with GSTM1-present allele showed a significantly diminished risk of mortality compared to patients bearing the GSTM1-null allele among ESRD patients with a hazard ratio of 4.6242 (P < 0.0001). Thus, present data confirm that GSTM1-null genotype increased the risk for all-cause rapid disease progression to ESRD among ND patients. Based on our results, GSTM1-null genotype could be considered as a significant predictor for causing mortality among CKD patients when compared to all other variables.

Early life acetaminophen exposure, glutathione S-transferase genes, and development of adolescent asthma in a high-risk birth cohort

Although the impact of early life acetaminophen on asthma risk is still not clear, potential interactions with glutathione S-transferase (GST) genes due to reduced antioxidant function in particular polymorphisms, and possible impact on lung function, have never been investigated in adolescents. We aimed to investigate associations between early life acetaminophen use and adolescent asthma and lung function and to assess potential interactions by GST polymorphisms. Acetaminophen use was recorded 18 times up to age 2 years (n= 575 [92.7%]). Participants were genotyped for GST polymorphisms (GSTM1/T1/P1) (n= 429 [69.2%]). Asthma and lung function were measured at 12 (n= 365 [58.9%]) and 18 years (n= 413 [66.6%]). Regression models assessed associations and interactions. Doubling of days of acetaminophen use was associated with reduced prebronchodilator FEV1/forced vital capacity (βcoefficient, -0.10; 95% CI, -0.19 to -0.01) and midexpiratory flow (-0.09; 95% CI, -0.18 to 0) at 18 years, but this association was not found when restricted for nonrespiratory reasons, suggesting confounding by indication. However, in children with GSTM1 null and GSTT1 present, increasing acetaminophen use for nonrespiratory reasons was associated with reduced FEV1 and midexpiratory flow at 18 years (interaction between GSTM1/T1 and acetaminophen P< .05). Increased acetaminophen use was associated with asthma at 18 years for children with GSTP1 Ile/Ile (odds ratio, 1.66; 95% CI, 1.07 to 2.57), but not other GSTP1 genotypes. These novel findings need to be investigated for consistency in other studies but suggest that children carrying risk genotypes may be susceptible to respiratory consequences from acetaminophen use.

Genetic Polymorphisms of Glutathione S-Transferase and Risk of Acute Myeloid Leukemia: Case-Control Study and Meta-Analysis

Background: Acute myeloid leukemia (AML) is a complex disease that is linked to genetic and environmental factors. The gluthatione S-transferase (GST) is a family of enzymes that play a crucial role in the detoxification of carcinogens. These compounds could cause DNA damage, which might lead to the development of cancer. Interindividual inherited differences caused by the presence of single nucleotide polymorphisms (SNPs) in detoxification enzyme, could play a major role in cancer predisposition. The present study aimed to investigate the association between GST gene polymorphisms and AML risk. Methods: The GSTP1 genotype was determined by the PCR-RFLP and multiplex PCR for GSTT1 and GSTM1. Meta-analysis was conducted to evaluate the association between GST gene and the risk of AML. Results: We found that GSTT1 null genotype was significantly associated with the risk of AML. However, GSTM1 and GSTP1 polymorphisms did not influence the AML risk. Subjects carrying the GSTM1 Present, GSTT1 null and GSTP1 Ile / Val et Val /Val genotypes had a higher risk of developing AML. The results of meta-analysis showed a positive association between GSTM1 null, GSTT1 null and Ile105Val GSTP1 polymorphisms and AML risk in East Asians, Caucasians, and mixed populations, respectively. Conclusion: GST gene polymorphisms may be risk factors for acute myeloid leukemia.

Polymorphism of glutathione S-transferase in the population of Polish patients with carcinoma of the prostate

The aim of the study was frequency analysis of GSTM1, GSTT1, and GSTP1 polymorphisms of glutathione S-transferase in the group of patients with prostate cancer and in a control group of healthy individuals. Genomic DNA was isolated; molecular analysis of glutathione S-transferase M1 and T2 polymorphisms was performed using multiplex PCR and RFLP methods. The products of the PCR reaction were then visualized in agarose gel, and a statistical analysis of the results was performed. No statistically significant differences were found in the frequency of glutathione S-transferase polymorphisms between 66 patients with prostate cancer and the control group (64 healthy volunteers). The GSTM1 gene deletion was found in ca. 47% of patients with prostate cancer and in ca. 55% of the controls. The GSTT1 deletion was found in approximately 17% of patients and 14% of the controls. The distribution of GSTP1 Ile/Ile, Ile/Val, and Val/Val polymorphisms was ca. 51.5%, 39%, and 9% in the group of patients and 61%, 34%, and 5% in the control group, respectively. The results indicate that there is no relationship between glutathione S-transferase polymorphisms and prostate cancer in the study group, which is a novelty when compared with the previous work on the role of these genetic variants in the etiology of cancer.

Correlation of GSTP1 gene variants of male Iraqi waterpipe (Hookah) tobacco smokers and the risk of lung cancer.

Glutathione-S-transferases (GSTs) play a role in the detoxification of environmental chemicals and mutagens, such as those inhaled during tobacco smoking. There have been conflicting reports concerning GST polymorphisms as risk factors in the development of lung cancer. No studies focused on Arab populations exposed to Waterpipe (WP) tobacco smoke have been undertaken. Here Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and gene sequencing were applied to analyze allelic variations in GSTP1-rs1695 and -rs1138272 amongst 123 lung cancer patients and 129 controls. The data suggest that WP smoking raised the risk of lung cancer more than three-fold (OR 3.6; 95% CI 2.1-6.0; p < 0.0001). However, there was no significant association between individual GSTP1 polymorphisms and the risk of lung cancer. In contrast, analysis of the rs1695 and rs1138272 combination suggested that the risk of lung cancer was raised more than two-fold for carriers of the GSTP1-rs1695 (G) allele (OR 2.5; 95% CI 1.0-6.4; p < 0.05), however, the presence of the GSTP1-rs1138272 (T) allele, in addition to GSTP1-rs1695, did not significantly change the risk ratio (OR 2.8; 95% CI 1.4-5.7; p < 0.004). WP tobacco smokers who carried the GSTP1-rs1695, but not GSTP1-rs1138272, allele were similarly susceptible to lung cancer (OR 2.4; 95% CI 1.1-5.3; p < 0.03). Hence, the results suggest that smoking WP tobacco and carrying GSTP1-rs1695 polymorphisms are risk factors for lung cancer in Arab Iraqi males.

Association Between Glutathione S-Transferase (GST) Polymorphisms and Schizophrenia in a Chinese Han Population.

BackgroundGlutathione S-transferase (GST) is an important antioxidant enzyme in the body. The weakening of the antioxidant system causes damage to the cells and tissues that make up the organism, adversely affects the function of the nervous system, and ultimately leads to schizophrenia (SCZ). Previous studies have yielded inconsistent results across different ethnic populations.PurposeThis case–control study was carried out to investigate whether genetic polymorphisms in GST could be associated with SCZ in the Chinese Han population.Patients and MethodsA total of 794 participants, including 379 SCZ patients (case group) and 415 healthy individuals (control group), were genotyped by polymerase chain reaction-restriction fragment length for polymorphisms in GST genes.ResultsThe study found that the frequency of the GSTM1 null genotype was higher in case group than control group (p=0.003). The frequency of the GSTM1 and GSTT1 double null genotype was also higher in case group than control group (p=0.008).ConclusionWe conclude that the GSTM1 null genotype and the GSTM1 and GSTT1 double null genotype may be related to the onset of SCZ in Chinese Han population.

Association between Polymorphisms of Glutathione S-Transferase and Progression to Cervical Cancer in Women from Burkina Faso and Mali

Although persistence of high-risk human papillomavirus infection is the main risk factor, Glutathione S-Transferase highly polymorphic enzyme involved in the metabolism of xenobiotics, is a good candidate gene. The objective of this study was to compare the polymorphisms of Glutathione S-Transferase M1-null in women with cancerous lesions and without lesions. This study consisted of 322 uterine cervix samples of women from Mali and Burkina Faso with Cervical Intra-epithelial Neoplasia 2 and 3, adenocarcinoma and squamous cell carcinoma and 100 women with no lesions. Human Papillomavirus genotyping was performed by Real-time multiplex Polymerase Chain Reaction. Glutathione S-Transferase gene polymorphisms were determined using conventional Polymerase Chain Reaction followed by migration on agarose gel. A statistically significant association with high relative risks of 10.77 for the development of High grade Superficial or Squamous Intra-epithelial Lesion (95% CI = 5.59 - 20.72; p < 0.001), and 13.20 for cancer development (95% CI = 6.79 - 25.63; p < 0.001) was found in women with the null genotype of Glutathione S-Transferase M1 in the study population. In Burkina Faso and Mali, Glutathione S-Transferase M1-null presented relative risks of 9 and 11.05 for high-grade lesions, 15 and 11.40 for cancer. Similarly, significant results had been observed in women with human papillomavirus positive and human papillomavirus negative. The results of the present study support the idea that the deletion of Glutathione S-Transferase M1 plays a crucial role in the progression of high-grade lesions and cervical cancer.

Glutathione S-transferase (GSTT1 and GSTP1) Polymorphisms Improves the Short- and Long-Term Efficacy of Concurrent Chemoradiotherapy in Advanced Ovarian Cancer

Glutathione S-transferase (GSTT1 and GSTP1) Polymorphisms Improves the Short- and Long-Term Efficacy of Concurrent Chemoradiotherapy in Advanced Ovarian Cancer

GSTs (T1 and M1) population data in patients with glaucoma: genetic screening and ethical aspects

Background and Aim: Molecular epidemiology is an interdisciplinary field concerning the analysis of biological indicators and the investigation of individual DNA polymorphisms. The glutathione-S-transferases (GSTs) are one of the most studied metabolic gene families. They are involved in the genesis of oxidative stress and many authors hypothesize that some null polymorphic variants determine increasing toxic effects in tissues. Oxidative stress and antioxidant systems are very important in the onset and progress of glaucoma, one of the leading causes of blindness worldwide. We investigate the association of null variant of GST (M1 and T1) with the risk of primary open angle glaucoma (POAG) and we considered the ethical and legal implications of genetic procedures as a screening tool. Materials and Methods: We conducted a case-control study including 103 unrelated carriers of glaucoma in a southern Italian population (living in Eastern Sicily) and 150 unrelated healthy individuals as controls, whose buccal swabs samples were genotyped for GST polymorphisms using a standardized multiplex PCR based method. Results: In patients with glaucoma (primary open angle glaucoma, POAG) null genotype of the investigated genetic polymorphisms is very common compared to the healthy individuals. The obtained data suggest an influence of the (dual) null genotype on the normal metabolic pathway in the genesis of congenital glaucoma giving to these polymorphisms the role of so-called “indicators of susceptibility”. Conclusions: We conclude that the increased frequency of null GSTs (M1, T1) in patients with glaucoma could be considered a risk factor for incidence of the disease. Screenings can be carried out only in compliance with legislative rules. Keywords: Glaucoma; Glutathione S-transferase; GSTM1; GSTT1

Association between genetic polymorphisms of glutathione S-transferase M1/T1 and psoriasis in a population from the area of the strict of messina (Southern Italy)

Glutathione S-transferases (GST) are antioxidant enzymes with frequent genetic polymorphisms. Homozygosis for gene deletion (“null” genotype) of GSTM1 and GSTT1, causing decrease of the antioxidant potential of the organism, is frequent, with variable frequency in different ethnic contexts. Although oxidative stress notoriously plays a role in the pathogenesis of psoriasis, few studies exist on the association between GSTM1/GSTT1 genotype and psoriasis, with different results. We aimed to assess the frequency of GSTM1/GSTT1 polymorphisms in Southern Italian psoriatic patients and controls and investigate the association of the GSTM1/GSTT1 genotype with individual and disease parameters. To this aim, the GSTM1/GSTT1 genotype of 148 psoriatic patients and 148 age- and sex-matched controls was defined by PCR on oral mucosa cells. GSTT1 null was associated with psoriasis (55.4% of patients vs. 25% of controls, p = 9.58 × 10−8, odds ratio 3.73), while GSTM1 null was not. The GSTM1/GSTT1 “double null” genotype conferred an even higher odds ratio for psoriasis (5.94). The association between psoriasis and GSTT1 null was stronger in women (54.1% of patients vs. 19.7% of controls, p = 8.13 × 10−5) than in men (56.3% of patients vs. 28.7% of controls, p = 0.0002). No association was found between GSTM1/GSTT1 genotype and psoriasis severity, age of onset or comorbidities (psoriatic arthritis, metabolic syndrome). The remarkable differences among the few available data on the association between GSTM1/GSTT1 polymorphisms and psoriasis suggest the need for further studies, on different and larger populations, to improve knowledge on the pathogenesis of psoriasis and possibly provide more precise and personalised prevention and treatment in the future.

Carcinogen Metabolism Pathway and Tumor Suppressor Gene Polymorphisms and Gallbladder Cancer Risk in North Indians: A Hospital-Based Case-Control Study.

Background:Carcinogen metabolism pathway and tumor suppressor gene polymorphisms have been reported to be associated with increased gallbladder cancer risk. However, the association of genetic variants and gallbladder cancer risk in Indians are not well studied. We examined whether genetic polymorphisms of metabolic enzymes cytochrome P450 1A1 and glutathione S-transferase and tumor suppressor gene p53 (TP53) are associated with an increased risk of gallbladder cancer in North Indians. Methods:This hospital-based case-control study was conducted in 96 gallbladder cancer patients with gallstones (cases) and 93 cholelithiasis patients (controls) at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India from July 2014 through May 2017. Genomic DNA was extracted from white blood cells of each patient using a simple salting-out procedure. The genotypic frequencies of CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 polymorphisms were investigated using TaqMan SNP Genotyping Assay and GSTM1 and GSTT1 polymorphisms were analyzed using the multiplex PCR assay. Results:The frequency of CC genotype of TP53 rs1042522 polymorphism was 27.1% (26/96) in cases and 12.9% (12/93) in controls. The CC genotype was associated with an increased risk of gallbladder cancer in North Indians (age- and sex-adjusted odds ratio, 2.81; 95% confidence interval, 1.19–6.61; P = 0.02). No significant differences in genotypic and allelic frequencies of the metabolic pathway gene polymorphisms were found between cases and controls. Conclusions:Our data provide preliminary evidence that the CC genotype of the TP53 rs1042522 polymorphism may be associated with an increased risk of gallbladder cancer in North Indians.

Beyond detoxification: Pleiotropic functions of multiple glutathione S-transferase isoforms protect mice against a toxic electrophile.

Environmental and endogenous electrophiles cause tissue damage through their high reactivity with endogenous nucleophiles such as DNA, proteins, and lipids. Protection against damage is mediated by glutathione (GSH) conjugation, which can occur spontaneously or be facilitated by the glutathione S-transferase (GST) enzymes. To determine the role of GST enzymes in protection against electrophiles as well as the role of specific GST families in mediating this protection, we exposed mutant mouse lines lacking the GSTP, GSTM, and/or GSTT enzyme families to the model electrophile acrylamide, a ubiquitous dietary contaminant known to cause adverse effects in humans. An analysis of urinary metabolites after acute acrylamide exposure identified the GSTM family as the primary mediator of GSH conjugation to acrylamide. However, surprisingly, mice lacking only this enzyme family did not show increased toxicity after an acute acrylamide exposure. Therefore, GSH conjugation is not the sole mechanism by which GSTs protect against the toxicity of this substrate. Given the prevalence of null GST polymorphisms in the human population (approximately 50% for GSTM1 and 20–50% for GSTT1), a substantial portion of the population may also have impaired acrylamide metabolism. However, our study also defines a role for GSTP and/or GSTT in protection against acrylamide mediated toxicity. Thus, while the canonical detoxification function of GSTs may be impaired in GSTM null individuals, disease risk secondary to acrylamide exposure may be mitigated through non-canonical pathways involving members of the GSTP and/or GSTT families.