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This work is the next step in studying the interplay between C-2028 (anticancer-active unsymmetrical bisacridine developed in our group) and the glutathione S-transferase/glutathione (GST/GSH) system. Here, we analyzed the concentration- and pH-dependent GSH conjugation of C-2028 in rat liver microsomes and cytosol. We also applied three recombinant human GST isoenzymes, which altered expression was found in various tumors. The formation of GSH S-conjugate of C-2028 in liver subfractions followed Michaelis-Menten kinetics. We found that C-2028 was conjugated with GSH preferentially by GSTM1-1, revealing a sigmoidal kinetic model. Using a colorimetric assay (MTT test), we initially assessed the cellular GST/GSH-dependent biotransformation of C-2028 in relation to cytotoxicity against Du-145 human prostate cancer cells in the presence or absence of the modulator of GSH biosynthesis. Pretreatment of cells with buthionine sulfoximine resulted in a cytotoxicity decrease, suggesting a possible GSH-mediated bioactivation process. Altogether, our results confirmed the importance of GSH conjugation in C-2028 metabolism, which humans must consider when planning a treatment strategy. Finally, nuclear magnetic resonance spectroscopy elucidated the structure of the GSH-derived product of C-2028. Hence, synthesizing the compound standard necessary for further advanced biological and bioanalytical investigations will be achievable. [ABSTRACT FROM AUTHOR]

This work is the next step in studying the interplay between C-2028 (anticancer-active unsymmetrical bisacridine developed in our group) and the glutathione S-transferase/glutathione (GST/GSH) system. Here, we analyzed the concentration- and pH-dependent GSH conjugation of C-2028 in rat liver microsomes and cytosol. We also applied three recombinant human GST isoenzymes, which altered expression was found in various tumors. The formation of GSH S-conjugate of C-2028 in liver subfractions followed Michaelis-Menten kinetics. We found that C-2028 was conjugated with GSH preferentially by GSTM1-1, revealing a sigmoidal kinetic model. Using a colorimetric assay (MTT test), we initially assessed the cellular GST/GSH-dependent biotransformation of C-2028 in relation to cytotoxicity against Du-145 human prostate cancer cells in the presence or absence of the modulator of GSH biosynthesis. Pretreatment of cells with buthionine sulfoximine resulted in a cytotoxicity decrease, suggesting a possible GSH-mediated bioactivation process. Altogether, our results confirmed the importance of GSH conjugation in C-2028 metabolism, which humans must consider when planning a treatment strategy. Finally, nuclear magnetic resonance spectroscopy elucidated the structure of the GSH-derived product of C-2028. Hence, synthesizing the compound standard necessary for further advanced biological and bioanalytical investigations will be achievable.

Abstract Background Colon adenocarcinoma (COAD) is the most common form of colon cancer. The glutathione S-transferase Mu (GSTM) gene belongs to the GST gene family, which functions in cell metabolism and detoxification. The relationship between GSTM and COAD and the underlying mechanism remain unknown. Methods Data extracted from The Cancer Genome Atlas included mRNA expression and clinical information such as gender, age, and tumor stage. Prognostic values of GSTM genes were identified by survival analysis. Function and mechanism of prognostic GSTM genes were identified by gene set enrichment analysis. A nomogram was used to predict the contribution of risk factors to the outcome of COAD patients. Results Low expression of GSTM1 and GSTM2 was related to favorable OS (adjusted P = 0.006, adjusted HR = 0.559, 95% CI = 0.367–0.849 and adjusted P = 0.002, adjusted HR = 0.519, 95% CI = 0.342–0.790, respectively) after adjusting for tumor stage. Enrichment analysis also showed that genes involved were related to cell cycle, metabolism, and detoxification processes, as well as the Wnt signaling and NF-κB pathways. Conclusions In conclusion, low expression of GSTM1 and GSTM2 were significantly associated with favorable prognosis in COAD. These two genes may serve as potential biomarkers of COAD prognosis.

Background: Colon adenocarcinoma (COAD) is the most common form of colon cancer. The glutathione S-transferase Mu (GSTM) gene belongs to the GST gene family, which functions in cell metabolism and detoxification. The relationship between GSTM and COAD and the underlying mechanism remain unknown. Methods: Data extracted from The Cancer Genome Atlas included mRNA expression and clinical information such as gender, age, and tumor stage. Prognostic values of GSTM genes were identified by survival analysis. Function and mechanism of prognostic GSTM genes were identified by gene set enrichment analysis. A nomogram was used to predict the contribution of risk factors to the outcome of COAD patients. Results: Low expression of GSTM1 and GSTM2 was related to favorable OS (adjusted P = 0.006, adjusted HR = 0.559, 95% CI = 0.367–0.849 and adjusted P = 0.002, adjusted HR = 0.519, 95% CI = 0.342–0.790, respectively) after adjusting for tumor stage. Enrichment analysis also showed that genes involved were related to cell cycle, metabolism, and detoxification processes, as well as the Wnt signaling and NF-κB pathways. Conclusions: In conclusion, low expression of GSTM1 and GSTM2 were significantly associated with favorable prognosis in COAD. These two genes may serve as potential biomarkers of COAD prognosis. [ABSTRACT FROM AUTHOR]

Allergic asthma is a diverse chronic respiratory disease characterized by the inflammation of the lower airway disease affecting many people around the world with rising morbidity and mortality. Association between asthma and certain demographic features was studied in relation to genotype from 244 allergic individuals of local population. Skin prick test was used to confirm asthma. Genetic polymorphism in Glutathione-S-transferases (GSTs) was studied using multiplex PCR based method and IgE level by ELISA. Pollen and dust were the major causative aeroallergens (26%), which were associated to higher IgE levels (P

We studied cancer patients for possible PAH exposure, using urinary concentration of 1-hydroxypyrene (1-OHP) as a biomarker of internal dose of polycyclic aromatic hydrocarbons (PAHs). The subjects included in this study belonged to various socio-demographic backgrounds, and were diagnosed with cancer (i.e. lung, head and neck or digestive tract cancer). In general, we observed high concentration of urinary 1-OHP among digestive tract cancer patients, compared with the controls (CN) (mean 1.06, median 1.03 and mean 0.62, median 0.63 μmol/mol-Cr in digestive tract cancer patients and controls respectively). The concentrations of urinary 1-OHP were higher than the background level of PAHs; therefore, these groups could have been exposed to PAHs. Highest urinary 1-OHP concentration was observed in digestive tract cancer patients (median 1.25 μmol/mol-Cr) with GSTM-1 genotype. The results of PCA were consistent with qualitative and quantitative data analysis. The contribution of urinary 1-OHP eigenvector revealed a relatively high PAH-exposure among cancer patients compared with CN, while diet and age were influential parameters among cancer patients, which could have a strong link in cancer etiology in the selected exposure groups. [ABSTRACT FROM AUTHOR]

We tested in this study whether the polymorphisms of the glutathione S-transferase Mu1 (GSTM1), glutathione S-transferase Theta 1 (GSTT1) and glutathione S-transferase Pi 1 (GSTP1), involved in metabolism of chemical agents, cell proliferation and cell survival, alter the risk for Hodgkin lymphoma (HL). Genomic DNA from 110 consecutive patients with HL and 226 controls was analysed by polymerase chain reaction and restriction digestion for the polymorphism analyses. Similar frequencies of the GSTM1 and GSTT1 genotypes were seen in patients and controls. In contrast, the frequency of the GSTP1 wild genotype (59.1%versus 36.3%, P = 0.004) was higher in patients than in controls. Individuals with the wild genotype had a 2.68 (95%CI: 1.38-5.21)-fold increased risk for the disease than others. An excess of the GSTP1 wild genotype was also observed in patients with tumors of stages III + IV when compared with those with tumors of stages I + II (39.1%versus 20.0%, P = 0.03). These results suggest that the wild allele of the GSTP1 gene is linked to an increased risk and high aggressiveness of the HL in our cases but they should be confirmed by further studies with larger cohorts of patients and controls. [ABSTRACT FROM AUTHOR]

The human GSTM gene family is composed of five gene members, GSTM1–5, and plays an important role in detoxification. In this study, the human GSTM5 gene was found to have a long inverted repeat (LIR) in intron 5. The LIR is able to form a stem-loop structure with a 31-bp stem and a 9-nt loop. The intronic LIR was also identified in other primates but not in non-primates. The human and chimpanzee LIRs had undergone compensating mutations that make the stem loop more stable, suggesting a functional role for the LIR. Sequence homology showed that the LIR was actually a part of inverted exons acquired by the intron. Results of phylogenetic analysis indicate that the inverted exons were derived from exon 5 of GSTM4 and exon 5 of GSTM1. The intronic LIR and inverted GSTM exons can probably introduce complexity in the expression of GSTM gene family.Journal of Human Genetics (2009) 54, 271–276; doi:10.1038/jhg.2009.23; published online 20 March 2009 [ABSTRACT FROM AUTHOR]

Background and Objective: Myelodysplastic syndromes (MDS) are clonal disorders of bone marrow stem cells characterized by ineffective hematopoiesis leading to blood cytopenia; they often progress to acute myeloid leukemia (AML). The glutathione S-transferases (GST) detoxify various agents, including those implicated in MDS. Both GSTM[sub 1] and GSTT[sub 1] genes have ‘null’ alleles and are polymorphic. We studied the impact of GTM[sub 1] and GSTT[sub 1] null genotypes on the MDS susceptibility, disease severity and laboratory indices with prognostic value for the syndrome. Material and Methods: In a hospital-based case-control study we analyzed lymphocyte DNA samples from 54 patients with MDS and 60 cancer-free controls matched for age, sex, smoking habits and origin. A multiplex polymerase chain reaction was used to genotype both GSTM[sub 1] and GSTT[sub 1] simultaneously. The χ[sup 2] test was used for statistical evaluation of the data and the odds ratios and attributable risk and population attributable risk were also calculated. Results: A significantly increased frequency of GSTM[sub 1] null genotype was found among MDS patients (57.4%) compared to controls (33.3%) (p < 0.01), while the frequency of GSTT[sub 1] null genotype was not significantly higher in MDS patients (11.1% vs. 6.66%). Neither GSTM[sub 1] and GSTT[sub 1] null genotype was associated with a particular category of the French-American-British (FAB) classification in the patients studied. Additionally, GSTM[sub 1] null genotype was associated with a significant decrease in the absolute number of neutrophils among the MDS patients. Conclusions: Individuals with GSTM[sub 1] null genotype may have increased susceptibility to MDS. Null genotypes do not seem to have be associated with FAB classification while they may be associated with putative prognostic factors.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract Background Extensive genome-wide analyses of many human populations, using microarrays containing hundreds of thousands of single-nucleotide polymorphisms, have provided us with abundant information about global genomic diversity. However, these data can also be used to analyze local variability in individual genomic regions. In this study, we analyzed the variability in two genomic regions carrying the genes of the GSTA and GSTM subfamilies, located on different chromosomes. Results Analysis of the polymorphisms in GSTA and GSTM gene clusters showed similarities in their allelic and haplotype diversities. These patterns were similar in three Russian populations and the CEU population of European origin. There were statistically significant differences in all the haploblocks of both the GSTM and GSTA regions when the Russian populations were compared with populations from China and Japan. Most haploblocks also differed between the Russians and Nigerians from Yoruba, but, some of them had similar allelic frequencies. Special attention was paid to SNP rs4986947 from the intron of the GSTA4 gene, which is represented in apes by an A nucleotide. In the Asian and African samples, it was represented only by a G allele, and both allelic variants (G/A) occurred in the Russian and European populations. Conclusions The results obtained suggest the presence of common features in the evolutionary histories of the GSTA and GSTM gene regions, and that African subpopulations were involved differently in the formation of the European and Asian human lineages.

Allergic asthma is a diverse chronic respiratory disease characterized by the inflammation of the lower airway disease affecting many people around the world with rising morbidity and mortality. Association between asthma and certain demographic features was studied in relation to genotype from 244 allergic individuals of local population. Skin prick test was used to confirm asthma. Genetic polymorphism in Glutathione-S-transferases (GSTs) was studied using multiplex PCR based method and IgE level by ELISA. Pollen and dust were the major causative aeroallergens (26%), which were associated to higher IgE levels ( P  < 0.05). Smoking was found to be significantly associated with asthma in only males ( P  = 0.004). A low prevalence of null genotype of both GSTM1 and GSTT1 genes was observed in the patients (4.34%) compared to control group (14%). No association of combined GSTM1 and GSTT1 null genotype was found with the asthma in local population. GSTM1+ and GSTT- genotype had higher risk (OR = 1.3681, P  = 0.001) for development of asthma. There was a significant association of asthma with combined genotype of GSTM1+ and GSTT- when data was analyzed on gender basis in males ( P  = 0.006) and highly significant in age range of 26-40 years ( P  = 0.001). Combined GSTM + and GSTT - genotype was found to be risk factor for asthma in addition to family history in male patients. However a data with large patient size and different ethnic distribution may reveal the exact etiology.

Background: Sensitization to cockroach is one of the strongest identified risk factors for greater asthma morbidity in low-income urban communities; however, the timing of exposures relevant to the development of sensitization has not been elucidated fully. Furthermore, exposure to combustion byproducts, including polycyclic aromatic hydrocarbons (PAHs), can augment the development of allergic sensitization. Objective: We sought to test the hypotheses that domestic cockroach allergen measured prenatally would predict cockroach sensitization in early childhood and that this association would be greater for children exposed to higher PAH concentrations. Methods: Dominican and African American pregnant women living in New York City were enrolled. In the third trimester expectant mothers wore personal air samplers for measurement of 8 nonvolatile PAHs and the semivolatile PAH pyrene, and dust was collected from homes for allergen measurement. Glutathione-S-transferase μ 1 (GSTM1) gene polymorphisms were measured in children. Allergen-specific IgE levels were measured from the children at ages 2, 3, 5, and 7 years. Results: Bla g 2 in prenatal kitchen dust predicted cockroach sensitization at the ages of 5 to 7 years (adjusted relative risk [RR], 1.15; P = .001; n = 349). The association was observed only among children with greater than (RR, 1.22; P = .001) but not less than (RR, 1.07; P = .24) the median sum of 8 nonvolatile PAH levels. The association was most pronounced among children with higher PAH levels and null for the GSTM1 gene (RR, 1.54; P = .001). Conclusions: Prenatal exposure to cockroach allergen was associated with a greater risk of allergic sensitization. This risk was increased by exposure to nonvolatile PAHs, with children null for the GSTM1 mutation particularly vulnerable. [Copyright &y& Elsevier]

Background: Some studies suggested that Glutathione S-transferases M1/T1(GSTM1/T1) null polymorphisms may be associated with the risk of vitiligo., Aims: The purpose of this study is to further evaluate the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo., Methods: We carried out a retrieval of studies in the databases. Odds ratios (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of this association. We analyzed the data using Stata 11.0., Results: Six case-control studies including 1358 cases and 1673 controls were included in this meta-analysis. Our overall results showed the GSTM1 or GSTT1 null polymorphism was associated with vitiligo (GSTM1:OR=1.59, 95% CI: 1.21-2.08, P=0.001; GSTT1: OR=1.30, 95% CI: 1.12-1.51, P=0.001). In the subgroup analysis, the GSTM1 null polymorphism might be a genetic risk factor to vitiligo in East Asian (OR=1.71, 95% CI: 1.12-2.63, P=0.014) but not in the Mediterranean, however individuals with the GSTT1 null polymorphism in the Mediterranean (OR=1.76, 95% CI: 1.15-2.71, P=0.010) but not in East Asian have a greater predisposition to vitiligo. In addition there was also a significant trend toward an association with the combination of the GSTM1 null and GSTT1 null in either East Asians or Mediterraneans., Conclusion: The GSTM1/T1 null polymorphisms may be associated with vitiligo. More studies are needed to confirm this conclusion., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Genetic polymorphisms of glutathione S-transferases (GSTs) and type 2 diabetes mellitus (T2DM) risk have been widely studied, however, the results were somewhat conflicting. To evaluate the association of GSTs (GSTM1, GSTT1 and GSTP1) gene polymorphisms with T2DM, a meta-analysis was performed before October, 2012. ORs were pooled according to random-effects model. There were a total of 1354/1666 (n=9) cases/controls (studies) for GSTM1, 1271/1470 (n=8) for GSTT1, and 1205/1250 (n=7) for GSTM1. There were significant associations between GSTM1 polymorphism, GSTT1 polymorphism and T2DM in the contrast of present genotype vs. null genotype, with pooled OR=1.99 (95%CI=1.46-2.71) and OR=1.61 (95%CI=1.19-2.17), respectively. Yet no significant association of GSTP1 polymorphism and T2DM was showed. When stratified by ethnicity, the significant associations were also existed in Asians for GSTM1 and GSTT1, but not GSTP1. No publication bias but some extent of heterogeneity was observed. Finally, the accumulated evidence proved the obvious associations of GSTM1 and GSTT1 polymorphisms with an increased risk of T2DM., (© 2013.)