Glutathione S-transferase Status Research Articles

Role of Glutathione-S-Transferase Polymorphism on Arsenic-Induced Protein Carbonylation and Urinary Deoxy Guanosine Status

Oxidative stress is significantly associated with chronic arsenic exposure in persons exposed to moderate-to-high level of environmental arsenic. However, the response varies widely among persons within similar exposure level. To study whether Glutathione-S-Transferase (GST) gene polymorphism plays any pivotal role in this variation, total number of 115 chronic arsenic-exposed study subjects without arsenic-induced cancer from School of Tropical Medicine, Kolkata and from arsenic-exposed districts of West Bengal were recruited for this study. Concentration of arsenic in their urine and water, extent of clinical manifestation, GST status and protein carbonylation, and 8-oxo-2′-deoxyguanosine status were determined. Genetic polymorphism of GSTM1 and T1 were significantly associated (p < 0.05) with degree of protein carbonylation and 8-oxo-2′-deoxyguanosine in moderate-to-high degree of arsenic exposure groups. Persons having null genotype have significantly increased level of protein carbonylation and 8-oxo-2′-deoxyguanosine in comparison to persons with GSTM1 or GSTT1 non-null genotype of the same arsenic exposure group. Degree of protein carbonylation and urinary 8-oxo-2-deoxyguanosine is positively correlated with GST null genotype.

Role of Glutathione-S-Transferase Polymorphism on Arsenic Induced DNA Hypermethylation

People chronically exposed to environmental arsenic through their drinking water experience various arsenic induced clinical manifestations and there is modulation of methylation level in their genome. However the response varies widely among persons. The present manuscript deals with the evaluation of role of individual's GST status in altering the degree of DNA methylation after chronic arsenic exposure in human. To study whether Glutathione-S-Transferase (GST) gene polymorphism plays any role in this variation, a total of 92 study subjects were recruited from the villages of southern region of West Bengal, India. Concentration of arsenic in their urine and water, extent of clinical manifestation, GST status and p53 and p16 gene promoter methylation status were determined. Results showed that genetic polymorphism of GSTM1 and T1 were significantly associated (p<0.05) with degree of methylation in p53 and p16 gene promoter region and urinary arsenic in higher exposure group. Persons having null genotype have significantly decreased urinary arsenic and increased DNA methylation level relative to persons with GSTM1 or GSTT1 nonnull genotype of same arsenic exposure group. In the present work we are therefore trying to show that individual's GST polymorphic status may alter the degree of DNA methylation after arsenic exposure.

Enhanced Growth-inhibitory Effect of Microemulsified Curcumin Formulation in Human Prostate Cancer LNCaP Cells

Aim: To assess the effect of curcumin microemulsified with non-ionic surfactant surfynol 465 W or dispersed using edible oils on prostate LNCaP cancer cell viability and glutathione status.Methodology: LNCaP cells were treated for 72-144 hr with curcumin dissolved with fish or corn oil and microemulsified using non-ionic surfactant surfynol 465 W; alternatively LNCaP cells were treated with curcumin directly dispersed in fish or corn oil (0-50 μM) for 24 -72-144 hr. Cell viability was determined using resazurin (Vision blueTM) fluorescence assay. Glutathione status was determined by monochlorobimane (MCB) assay.Results: Treatment with 0-34 μM of microemulsified curcumin produced moderate cytotoxic effect on LNCaP cells, no 50% reduction of cell viability was observed graphically. However, when LNCaP cells were treated with curcumin dispersed with corn oil the concentration or 50% reduction of cell viability (IC50) was 12-45 μM. Similarly for cells treated with curcumin dispersed with fish oil, the IC50 was between 20-40 μM. Cytotoxic doses of curcumin dispersed with corn or fish oil increased GST status in cells by 272-656% (p =<0.01).Conclusion: Microemulsified curcumin formulation prepared using fish or corn oil and surfynol 465 W surfactant had an inhibitory effect on viability of LNCaP cells as did direct dispersion of curcumin in fish or corn oil coupled with the ability for inducing intracellular GST status in LNCaP cells. Keywords : Curcumin; phase II enzymes; prostate cancer cells (LNCaP); glutathione (GSH); glutathione-S-transferase (GST); monochlorobimane (MCB); resazurin; fish oil; corn oil.- See more at: http://www.sciencedomain.org/abstract.php?iid=881&id=14&aid=7465#sthash.GPXT4ChK.dpuf

Glutathione S-transferase gene polymorphisms and susceptibility to chronic myeloid leukemia

Glutathione S-transferase (GST), a phase II metabolizing enzyme, plays an important role in the cellar defense system, and its activity may modulate leukemia risk. A large body of evidence has shown the possible relevance of functional polymorphisms of the genes that encode GSTs μ, π, and θ (GSTM1, GSTP1, and GST1, respectively) to the genetic susceptibility of chronic myeloid leukemia (CML). Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until December 20, 2013, and the extracted data were statistically analyzed using Review Manager version 5.2. Finally, 16 eligible studies were identified in the literature. The GSTT1 null genotype was associated with an increased risk of CML, as were the double null GSTT1 and GSTM1 genotypes. These findings suggest that heritable GST status influences the risk of developing CML and that more attention should be paid to carriers of these susceptibility genes.

GST polymorphic status modifying the arsenic induced clinical manifestations in people of the southern part of West Bengal, India

Persons chronically exposed to environmental arsenic through their drinking water experience various arsenic induced clinical manifestations which includes keratosis and pigmentary changes in the skin. However the response varies widely among persons. To study whether Glutathione-S-Transferase (GST) gene polymorphism plays any role in this variation, a total of 78 study subjects were recruited from the villages of southern region of West Bengal, India. Concentration of arsenic in their urine and drinking water were determined by Atomic Absorption Spectrophotometry Hydride Generation (AAS) system. Extent of clinical manifestations in the form of pigmentation and keratosis were determined by evaluation of the severity and giving clinical symptom score according to their degree of severity. The individual’s GST status was determined by multiplex PCR approach. The persons having skin manifestation given a score called clinical symptom score by which the degree of the clinical manifestation was determined. Results showed that genetic polymorphism of GSTM1 and T1 were significantly associated with urinary arsenic and clinical manifestation in higher exposure group. Persons having null genotype have significantly decreased urinary arsenic (p< 0.01) and increased clinical symptom (p<0.05) score relative to persons with GSTM1 or GST T1 non-null genotype of same arsenic exposure group. The study signifies that GST status determines the extent of biotransformation of arsenic in the body which further determines the degree of arsenic induced clinical manifestations in exposed persons. Key words: Arsenic, GST polymorphism, total urinary arsenic, clinical symptom score.

Effect of glutathione- S-transferase polymorphisms on the cancer preventive potential of isothiocyanates: An epidemiological perspective

Isothiocyanates (ITCs) are widely distributed in cruciferous vegetables and are biologically active against chemical carcinogenesis due to their ability to induce phase II conjugating enzymes. Among these is the glutathione- S-transferase (GST) family of enzymes, which in turn catalyzes the metabolism of ITCs, for which it has high substrate specificity. A recent body of epidemiologic data on the inverse association between cruciferous vegetable/ITC intake and cancers of the colo-rectum, lung and breast, also support that this protective effect is greater among individuals who possess the GSTM1 or T1 null genotype, and who would be expected to accumulate higher levels of ITC at the target tissue level, a pre-requisite for their enzyme-inducing effects. The association between ITC and cancer, and its modification by GST status, is most consistent for lung cancer and appears to be strongest among current smokers. Within limits, a comparison between groups which have been stratified by GST genotype may be less susceptible to confounding by other variables, given the random assortment of genes in gametogenesis. While a more complete understanding of the overall effects on health will need to take into account other components such as indoles and anti-oxidants, the interaction between ITC intake and GST genotype may provide a firmer basis to support a biologically significant role for ITC in cruciferous vegetables.

Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma.

Chronic infection with hepatitis B virus (HBV) causes DNA damage. An arginine (Arg)-to-glutamine (Gln) polymorphism at codon 399 in the XRCC1 gene is putatively associated with DNA damage. In a case-control study of 577 HBV surface antigen carriers with hepatocellular carcinoma (HCC) and 389 HBV carrier control subjects, we investigated the association between this polymorphism and the risk of HCC and assessed whether this association varied with glutathione S-transferase (GST) status; GSTs are involved in carcinogen metabolism. All statistical tests were two-sided. The XRCC1 Gln allele was associated with a dose-dependent increased risk of early-onset HCC (<50 years) but not with the risk of late-onset HCC (P(trend) =.01). The GSTT1-null genotype alone did not affect risk, but the GSTM1-null genotype was associated with a decreased risk for early-onset HCC. Various combinations of GSTM1 and GSTT1 genotypes differentially modified the association of XRCC1 with HCC (P(interaction) =.005); e.g., for individuals with the GSTT1-null/GSTM1-present genotype, the risk of HCC was greater for those with the Gln/Gln genotype (odds ratio = 8.07, 95% confidence interval = 1.67 to 38.93) than for those with the Arg/Arg genotype. Thus, GST status appears to affect the risk of HCC associated with this XRCC1 polymorphism.

ARE INDIVIDUALS WITH GLUTATHIONE S-TRANSFERASE GSTT1 NULL GENOTYPE MORE SUSCEPTIBLE TO IN VITRO OXIDATIVE DAMAGE?

Recent epidemiological studies proposed that glutathione S-transferase (GST) T1 null genotype was correlated with an increased susceptibility to diseases associated with oxidative stress, including cancer. A comparative study using erythrocytes from individuals with GSTT1 null genotype was carried out to determine how resistance to oxidative stress is affected by lack of this gene, and whether the GST status of a person is an important factor in risk toward oxidant chemicals. Malondialdehyde and carbonyl levels and fluorescence and chemilum inescence formation were used as biomarkers of oxidative stress in erythrocytes exposed in vitro to cumene hydroperoxide (CumOOH), an oxidizing agent. When peroxidation-dependent changes in these parameters were compared between GSTT1 null genotype and controls, who are both GSTM1 and GSTT1 positive, no significant differences were found between the two genotypes, although the erythrocytes of the GSTT1 null group had lower GSTT1 activity toward Cum OOH. Our results indicate that erythrocytes from individuals with GSTT1 null genotype are not abnorm ally susceptible to CumOOH-induced oxidant challenge.

Glutathione-S-Transferase in the Ageing Rat Brain Cerebrum and the Effect of Chlorpromazine

Lipid peroxidation increases during ageing and has been implicated in the pathogenesis of degenerative processes associated with ageing. Despite the importance of the enzyme glutathione-S-transferase (GST) in the biotransformation and detoxification of lipid peroxidation products, there have been extremely limited studies of GST in the ageing brain. The drug chlorpromazine is known to have an activating influence on the activities of certain antioxidant enzymes (glutathione peroxidase, superoxide dismutase, etc.) and it also has anti-lipid peroxidative and anti-lipofuscin influences. Therefore, information about the age-related changes in brain GST and the effect of chlorpromazine on it in the ageing brain will be of further interest. We have, therefore, studied the effect of age on the activity of GST in the whole homogenate and cytosol fractions from the cerebral hemispheres of rats aged 1, 2, 3, 6, 12, 18 and 24 months. The effect of chlorpromazine treatment (10 mg/kg i.p. on alternate days for 6 months) was examined in the whole homogenate and cytosol fraction from the cerebral hemispheres of 6-, 12-, 18- and 24-month-old rats. The results showed that the values for GST specific activities in the cytosol fraction from all the age groups were higher then those in the whole homogenate; and the pattern of age changes in the whole homogenate differed from that in the cytosol. In the cytosol fraction the enzyme activity showed several phases of alterations: a progressive increase at 3 months of age, followed by a steady level up to 12 months of age; this phase was folllowed by a fall in the activity (at 18 months of age) then turned to a gradual increase. In the whole homogenate there were two phases of alterations: a progressive increase up to 12 months of age, which then turned to a somewhat gradual decrease with ageing. Thus, the decline in GST activity during ageing was evident in both the whole homogenate and cytosol. The results from chlorpromazine experiments showed that the drug elevated the GST activity in 12-, 18-, and 24-month-old animals but not in the 6-month-old animals. The drug’s effects were most profound in 12-month-old animals. In conclusion, this study demonstrated an impairment of brain GST activity during ageing and the results further showed that the drug chlorpromazine attenuated the age-related impairment in the enzyme activity. The enhancement of the GST status of the ageing brain following chlorpromazine treatment is indicative of an additional antioxidative property of this drug.

Glutathione S-transferase activity in epithelial ovarian cancer: Association with response to chemotherapy and disease outcome

Conflicting data have been reported about the association between glutathione S-transferase (GST), a family of proteins implicated in detoxification of cytotoxic drugs in human ovarian in vitro models, and response to chemotherapy and prognosis in ovarian cancer patients. The aim of this study was to analyze the possible clinical role of GST activity in a large series of primary ovarian cancer patients. The study included a large series of primary untreated ovarian cancer patients who underwent cytoreductive surgery and chemotherapy and who were followed up in a single institution. GST activity levels were assessed in tumor extracts by using a biochemical assay. A cut-off of 250 units of enzymatic activity was chosen according to the receiver operating characteristics (ROC) curve. GST activity levels were distributed in an asymmetrical manner (median: 266 units; range: 4-918 units) and did not seem to be associated with stage, histopathological grading, ascites, or residual tumor after surgery. Higher GST activity levels were found in patients who responded to chemotherapy (median: 298 units, range: 50-691) than in those who responded only partially (median: 227 units, range: 19-747) or not at all to chemotherapy (median: 246 units, range: 4-811) (H = 7.02, P = 0.029). Moreover, the percentage of cases with > 250 units was significantly higher among complete responders (66%) than partial responders (37%) or non-responders (48%) (chi 2 = 7.32; P = 0.025). When multivariate analysis, including clinico-pathological parameters and GST activity status as predictors of response to chemotherapy, was carried out, residual tumor, stage and GST status retained independent predictive value. Patients with high GST activity had more favourable prognosis than those with low GST activity. The median PFS was 42 months for patients with high GST activity compared to 17 months for those with low GST activity (P = 0.037). The median overall survival was 72 months for high-GST-activity and 42 months for low-GST-activity patients (P = 0.043). Substantially similar results were obtained in the subgroup of stage II-III-IV ovarian cancer patients. Multivariate analysis including the clinico-pathological parameters and GST activity status was performed in stage III-IV ovarian cancer patients: Stage IV disease, residual tumor > 2 cm, the presence of ascites and low GST activity status retained independent negative prognostic roles. A direct association between high GST activity and a better clinical outcome in terms of response to chemotherapy and survival has been observed in a large series of primary untreated ovarian cancer patients. These results, which are contrary to the expectations raised by in vitro studies, emphasize the need for caution when translating in vitro-generated hypotheses to the clinical setting.