Glutathione S-transferase Family Research Articles

Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis

ObjectivesThe objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter...

A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactions.

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation toASD.

Hypomethylation of the GSTM1 promoter is associated with ovarian endometriosis.

Is the methylation status of the glutathione S-transferase M1 (GSTM1) promoter region altered in patients with ovarian endometriosis, and does this affect the expression of GSTM1 in their endometrial tissues? The promoter region of GSTM1 was significantly hypomethylated in the ectopic and eutopic endometrium of patients with ovarian endometriosis and this was associated with higher expression of GSTM1 mRNA. GSTM1, a member of the glutathione S-transferase family, is primarily known as a detoxification enzyme, but it has also been shown to negatively regulate apoptosis-related signalling cascades through protein-protein interactions with apoptosis signal-regulating kinase-1. This is a case-control study between September 2013 and December 2016, involving 65 patients with ovarian endometriosis and 53 women without endometriosis. We analysed the methylation status and expression levels of GSTM1 in the ectopic and eutopic endometrium of patients with ovarian endometriosis and the endometrium of women without endometriosis. In addition, we collected endometrial samples from 12 women without endometriosis for endometrial epithelial cell cultures. Methylation levels of the GSTM1 promoter region in the ectopic and eutopic endometrial tissues of patients with ovarian endometriosis and the endometrial tissues of women without endometriosis were analysed by pyrosequencing. The expression of GSTM1 mRNA and protein in endometrial tissues was investigated by RT-qPCR and immunohistochemistry, respectively. Primary cell culture, gene transfection, Cell Counting Kit-8 assay and flow cytometry were used to analyse the effect of GSTM1 on viability and apoptosis in endometrial epithelial cells. Compared with that in the endometrium of women without endometriosis, the GSTM1 promoter region was significantly hypomethylated in the ectopic and eutopic endometrium of patients with ovarian endometriosis. Additionally, GSTM1 mRNA and protein levels were significantly higher in the ectopic and eutopic endometrium than in the control endometrium. Moreover, the methylation levels of the GSTM1 promoter region were significantly negatively correlated with the mRNA expression of GSTM1. Furthermore, in vitro results suggested that the over-expression of GSTM1 could significantly increase viability and inhibit apoptosis in endometrial epithelial cells following hormone treatment and withdrawal. Due to restrictions in the isolation and culture of pure populations of endometrial epithelial cells, as well as limitations in the number of passages possible in primary cells, we could not explore the underlying molecular mechanism by which GSTM1 modulates apoptosis in endometrial cells. This study provides new evidence to support the notion that endometriosis may be an epigenetic disease. This work was supported by grants from the Natural Science Foundation of Hebei Province (Grant number: H2018206200) and the Department of Education of Hebei Province (Grant number: CXZZBS2017114). The authors have no conflicts of interest to declare.

Relevance of the intestinal health-related pathways to broiler residual feed intake revealed by duodenal transcriptome profiling

In broiler production, there is a continuous effort to breed feed efficient chickens. Residual feed intake (RFI) is an accurate indicator that has been accepted as an alternative measure of the conventional feed conversion ratio. This study conducted a duodenal transcriptome survey to explore the molecular basis of broiler RFI. Results showed that there are 599 genes that were differentially expressed (DE) in the duodenum between high RFI and low RFI (LRFI) broilers. Functional analysis showed that RFI can be explained by differences in the regulation of the immune system process, complement activation, nutrient digestion, and absorption pathways. Among those processes, the glutathione S-transferase family and serpin family are involved in glutathione metabolism and TGF-β signaling. These genes are involved in complement and coagulation cascade pathways that constitute a new regulatory network to reduce oxidative stress and inflammatory reaction, as well as to improve the defense capability in LRFI broilers. Ten DE genes related to the digestive tract health and digestive function, CCK, MPEG1, EPHB2, SERPINH1, VANGL2, CYFIP2, PCDH19, TGFBI, SCUBE3 and CATHL1, were identified as candidate genes related to RFI. In conclusion, the results indicate that there is less oxidative stress, less inflammatory reactions, and better digestion and absorption in the duodenum of the LRFI broilers, which might result in improved intestinal health and contribute to an increase in the efficiency of feed conversion.

Glutathione S-Transferase Genotype Protects against In Utero Tobacco–linked Lung Function Deficits

Rationale: In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.

A novel glutathione S-transferase gene from sweetpotato, IbGSTF4, is involved in anthocyanin sequestration

Anthocyanins are synthesized by multi-enzyme complexes localized at the cytoplasmic surface of the endoplasmic reticulum (synthesis site), and transported to the destination site, the vacuole. Three mechanisms for the vacuolar accumulation of anthocyanin in plant species have been proposed. Previous studies have indicated that glutathione S-transferase (GST) genes from model and ornamental plants are involved in anthocyanin transportation. In the present study, an anthocyanin-related GST, IbGSTF4, was identified and characterized based on transcriptome results. Phylogenetic analysis revealed that IbGSTF4 was most closely correlated to PhAN9 and CkmGST3, the anthocyanin-related GST of Petunia hybrida and Cyclamen. Furthermore, the expression analysis revealed that IbGSTF4 is strongly expressed in pigmented tissues, when compared to green organs, which is in agreement to the ability to correlate with anthocyanin accumulation. A GST activity assay uncovered that the IbGST4 protein owned similar activities with the GST family. Furthermore, the molecular functional complementation of Arabidopsis thaliana mutant tt19 demonstrated that IbGSTF4 might play a vital role in the vacuole sequestration of anthocyanin in sweetpotato. Moreover, the dual luciferase assay revealed that the LUC driven by the promoter of IbGSTF4 could not be directly activated by IbMYB1, suggesting that the regulatory mechanism of anthocyanin accumulation and sequestration in sweetpotato was intricate.

Individual stages of bacterial dichloromethane degradation mapped by carbon and chlorine stable isotope analysis

The fractionation of carbon and chlorine stable isotopes of dichloromethane (CH2Cl2, DCM) upon dechlorination by cells of the aerobic methylotroph Methylobacterium extorquens DM4 and by purified DCM dehalogenases of the glutathione S-transferase family was analyzed. Isotope effects for individual steps of the multi-stage DCM degradation process, including transfer across the cell wall from the aqueous medium to the cell cytoplasm, dehalogenase binding, and catalytic reaction, were considered. The observed carbon and chlorine isotope fractionation accompanying DCM consumption by cell supensions and enzymes was mainly determined by the breaking of CCl bonds, and not by inflow of DCM into cells. Chlorine isotope effects of DCM dehalogenation were initially masked in high density cultures, presumably due to inverse isotope effects of non-specific DCM oxidation under conditions of oxygen excess. Glutathione cofactor supply remarkably affected the correlation of variations of DCM carbon and chlorine stable isotopes (Δδ13C/Δδ37Cl), increasing corresponding ratio from 7.2–8.6 to 9.6–10.5 under conditions of glutathione deficiency. This suggests that enzymatic reaction of DCM with glutathione thiolate may involve stepwise breaking and making of bonds with the carbon atom of DCM, unlike the uncatalyzed reaction, which is a one-stage process, as shown by quantum-chemical modeling.

De novo transcriptomic analysis of the alimentary tract of the tephritid gall fly, Procecidochares utilis.

The tephritid gall fly, Procecidochares utilis, is an important obligate parasitic insect of the malignant weed Eupatorium adenophorum which biosynthesizes toxic secondary metabolites. Insect alimentary tracts secrete several enzymes that are used for detoxification, including cytochrome P450s, glutathione S-transferases, and carboxylesterases. To explore the adaptation of P. utilis to its toxic host plant, E. adenophorum at molecular level, we sequenced the transcriptome of the alimentary tract of P. utilis using Illumina sequencing. Sequencing and de novo assembly yielded 62,443 high-quality contigs with an average length of 604 bp that were further assembled into 45,985 unigenes with an average length of 674 bp and an N50 of 983 bp. Among the unigenes, 30,430 (66.17%) were annotated by alignment against the NCBI non-redundant protein (Nr) database, while 16,700 (36.32%), 16,267 (35.37%), and 11,530 (25.07%) were assigned functions using the Clusters of Orthologous Groups (COG), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases, respectively. Using the comprehensive transcriptome data set, we manually identified several important gene families likely to be involved in the detoxification of toxic compounds including 21 unigenes within the glutathione S-transferase (GST) family, 22 unigenes within the cytochrome P450 (P450) family, and 16 unigenes within the carboxylesterase (CarE) family. Quantitative PCR was used to verify eight, six, and two genes of GSTs, P450s, and CarEs, respectively, in different P. utilis tissues and at different developmental stages. The detoxification enzyme genes were mainly expressed in the foregut and midgut. Moreover, the unigenes were higher expressed in the larvae, pupae, and 3-day adults, while they were expressed at lower levels in eggs. These transcriptomic data provide a valuable molecular resource for better understanding the function of the P. utilis alimentary canal. These identified genes could be pinpoints to address the molecular mechanisms of P. utilis interacting with toxic plant host.

Molecular cloning, identification of GSTs family in sunflower and their regulatory roles in biotic and abiotic stress.

Glutathione-S-transferase (GST) genes exist widely in plants and play major role in metabolic detoxification of exogenous chemical substances and oxidative stress. In this study, 14 sunflower GST genes (HaGSTs) were identified based on the sunflower transcriptome database that we had constructed. Full-length cDNA of 14 HaGTSs were isolated from total RNA by reverse transcription PCR (RT-PCR). Sunflower was received biotic stress (Sclerotinia sclerotiorum) and abiotic stress (NaCl, low-temperature, drought and wound). GST activity was measured by using the universal substrate. The results showed that most of the HaGSTs were up-regulated after NaCl and PEG6000-induced stresses, while a few HaGSTs were up-regulated after S. sclerotiorum, hypothermia and wound-induced stressed, and there was correlation between the changes of GST activity and the expression of HaGSTs, indicating that HaGSTs may play regulatory role in the biotic and abiotic stress responses. 14 HaGSTs from sunflower were identified, and the expression of HaGSTs were tissue-specific and played regulatory roles in both stress and abiotic stress.

Characterization of the glutathione S-transferase (GST) gene family in Pyrus bretschneideri and their expression pattern upon superficial scald development

Glutathione S-transferases (GSTs) proposedly play a crucial role in the development of superficial scald in pear fruit; however, the specific member from pear GST gene family, which plays an important role in this process, has not been identified until recently. In this study, a total of 62 GST family genes were identified in Pyrus bretschneideri genome, which were distributed across the 14 chromosomes and 8 scaffolds with an uneven distribution. They could be categorized into eight classes based on phylogenetic analysis, and WGD/segmental duplication mainly drove their expansion. The expression of PbrGSTs in ‘Yali’ pear fruit was tissue-specific. In accompany with superficial scald development was the accumulation of reactive oxygen species (ROS) accumulation and loss of ascorbic acid (AsA) in the pericarp of ‘Yali’ pear. Of 47 PbrGSTs detected in the pericarp, the transcription of 25 members were enhanced upon the development of superficial scald, while three in dehydroascorbate reductase (DHAR) class were downregulated in association with lower DHAR activity. In combination with the results of the impact of 1-MCP and MHO fumigation on the expression profile of PbrGSTs, PbrDHAR1, PbrDHAR2 and PbrDHAR4 were selected as the candidate gene involved in superficial scald development.

Delineation of the functional and structural properties of the glutathione transferase family from the plant pathogen Erwinia carotovora

Erwinia carotovora, a widespread plant pathogen that causes soft rot disease in many plants, is considered a major threat in agriculture. Bacterial glutathione transferases (GSTs) play important roles in a variety of metabolic pathways and processes, such as the biodegradation of xenobiotics, protection against abiotic stress, and resistance against antimicrobial drugs. The GST family of canonical soluble enzymes from Erwinia carotovora subsp. atroseptica strain SCRI1043 (EcaGSTs) was investigated. Genome analysis showed the presence of six putative canonical cytoplasmic EcaGSTs, which were revealed by phylogenetic analysis to belong to the well-characterized GST classes beta, nu, phi, and zeta. The analysis also revealed the presence of two isoenzymes that were phylogenetically close to the omega class of GSTs, but formed a distinct class. The EcaGSTs were cloned and expressed in Escherichia coli, and their catalytic activity toward different electrophilic substrates was elucidated. The EcaGSTs catalyzed different types of reactions, although all enzymes were particularly active in reactions involving electrophile substitution. Gene and protein expression profiling conducted under normal culture conditions as well as in the presence of the herbicide alachlor and the xenobiotic 1-chloro-2,4-dinitrobenzene (CDNB) showed that the isoenzyme EcaGST1, belonging to the omega-like class, was specifically induced at both the protein and mRNA levels. EcaGST1 presumably participates in counteracting the xenobiotic toxicity and/or abiotic stress conditions, and may therefore represent a novel molecular target in the development of new chemical treatments to control soft rot diseases.

Molecular docking and assessment of thiacalix[4]arene and sulfonylcalix[4]arene as a platform for designing glutathione S-transferase inhibitors

It is known that overexpression of isozymes of glutathione S-transferase family is one of the causes for the resistance of cancer cells to the action of drugs. Therefore, inhibitors of these enzymes can be considered as potential drugs. Aim. To assess in silico calix[4]arene, thiacalix[4]arene, and sulfonyl alkyl[4]arene as a molecular platform for designing inhibitors of glutathione S-transferase. Results and discussion. Docking models of complexes of glutathione S-transferase with α-hydroxymethylphosphonate derivatives of calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene were calculated and analyzed. The binding models obtained by AutoDock 4.2 program were assessed by the molecular dynamics simulations. It has been shown that sulfonyl groups of the sulfonylcalix[4]arene macrocycle can be involved in additional stabilization of the enzyme-inhibitor complex. In addition, the affinity of the inhibitors to the enzyme depends on the stereoisomeric α-hydroxymethylphosphonate residues located at the upper rim of the macrocycle. Experimental part. Molecular docking of macrocyclic compounds to the active site region of glutathione S-transferase was performed using AutoDock 4.2 and AutoDock Vina. Molecular dynamics was modeled using NAMD 2.10 program. Conclusions. It has been determined that sulfonylcalix[4]arene can be a promising molecular platform for designing inhibitors of glutathione S-transferase.

Homozygous deletion of both GSTM1 and GSTT1 genes is associated with higher CD4+ T cell counts in Ghanaian HIV patients.

Glutathione S-transferase (GST) family of enzymes are involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogens and xenobiotics. The GST enzymes play important roles in oxidative stress pathways, and polymorphisms in the GSTM1 and GSTT1 genes mediate susceptibility and outcome in different diseases. Human immunodeficiency virus (HIV) infection is associated with oxidative stress, but there is limited data on the frequency of deleted GSTM1 and GSTT1 genes in HIV/AIDS patients and their effect on progression among Ghanaians. This study sought to investigate the association between homozygous deletion of GSTM1 and GSTT1 genes (both null deletion) with HIV/AIDS disease progression in Ghanaian patients. HIV-infected individuals on antiretroviral therapy (ART), ART-naïve HIV patients, and HIV seronegative individuals were recruited for the study. HIV/AIDS disease progression was assessed by measuring CD4+ cell count and viral load of the patients, and GST polymorphism was determined by amplifying the GSTT1 and GSTM1 genes using multiplex PCR, with CYP1A1 gene as an internal control. The mean CD4+ count of patients that were naïve to ART (298 ± 243 cells/mm3) was significantly lower than that of patients on ART (604 ± 294 cells/mm3), and viral load was significantly lower in the ART-experienced group (30379 ± 15073 copies/mm3) compared to the ART-naïve group (209882 ± 75045 copies/mm3). Frequencies of GSTM1 and GSTT1 deletions were shown to be 21.9% and 19.8%, respectively, in the HIV patients, and patients with homozygous deletion of both GSTM1 and GSTT1 were more likely to have their CD4+ count rising above 350 cells/mm3 (OR = 6.44, 95% CI = 0.81–51.49, p = 0.039) suggesting that patients with homozygous deletion of GSTM1 and GSTT1 genes have slower disease progression. The findings of this study show that double deletion of glutathione S-transferases M1 and T1 is statistically associated with normal CD4+ count in patients diagnosed with HIV/AIDS. Further study is required to investigate the clinical importance of the both null deletion in HIV patients.

Cruciferous Vegetables and Risk of Cancers of the Gastrointestinal Tract.

Cancers of the oropharyngeal tissues, oesophagus, stomach, and colorectum are amongst the most common causes of death from cancer throughout the world. Higher consumption of fruits and vegetables is thought to be protective, and cruciferous vegetables are of particular interest because of their unique role as a source of biologically active glucosinolate breakdown products. A literature review of primary studies and meta-analyses indicates that higher consumption of cruciferous vegetables probably reduces the risk of colorectal and gastric cancers by approximately 8% and 19%, respectively. Some studies support the hypothesis that the protective effect against colorectal cancer is modified by genetic polymorphisms of genes regulating the expression of enzymes of the glutathione S-transferase family, but due to contradictory findings the evidence is currently inconclusive. Despite these promising findings, future epidemiological research on the protective effects of cruciferous plants will depend critically upon accurate measurement of dietary exposure, both to the vegetables themselves, and to their active constituents. The development of sensitive chemical assays has facilitated the measurement of urinary excretion of isothiocyanate metabolites as an objective biomarker of intake, but sampling strategies need to be optimized in order to assess long-term exposures at the population level.

Effects of single and combined exposure of pharmaceutical drugs (carbamazepine and cetirizine) and a metal (cadmium) on the biochemical responses of R. philippinarum

In the aquatic environment, organisms are exposed to complex mixtures of contaminants which may alter the toxicity profile of each compound, compared to its toxicity alone. Pharmaceutical drugs (e.g. carbamazepine (CBZ) and cetirizine (CTZ)) and metals (e.g. cadmium (Cd)) are among those contaminants that co-occur in the environment. However, most studies concerning their toxicity towards aquatic species are based on single exposure experiments. Thus, the present study aimed to evaluate single and combined effects of Cd and CBZ or CTZ (single conditions: Cd, CTZ, CBZ; combined conditions: CTZ + Cd, CBZ + Cd) on biomarkers related to oxidative stress and energy metabolism in the edible clam Ruditapes philippinarum, by exposing the organisms for 28 days to environmentally relevant concentrations of these contaminants. The biomarkers studied were: i) the electron transport system activity, protein and glycogen contents (indicators of organisms’ metabolic status and energy reserves); ii) lipid peroxidation and the ratio between reduced and oxidized glutathione (indicators of oxidative stress); iii) superoxide dismutase and catalase activities (enzymes indicators of antioxidant defence) and iv) activity of glutathione S-transferases (family of enzymes indicators of biotransformation capacity). Results obtained showed that the uptake of Cd and CBZ was not affected by the combined presence of the contaminants. However, for CTZ, the uptake was higher in the presence than in the absence of Cd. Concerning toxicity data, in general, the combined exposures (CTZ + Cd, CBZ + Cd) had lower biological effects than the contaminants alone. Nevertheless, our data showed that despite the low concentrations tested, they were enough to exert biological effects that differed between single and combined treatments, evidencing the need to conduct more co-exposure studies to increase the environmental relevance of the gathered data.

Genome-Wide Identification, Characterization, and Expression Profiling of Glutathione S-Transferase (GST) Family in Pumpkin Reveals Likely Role in Cold-Stress Tolerance.

Plant growth and development can be adversely affected by cold stress, limiting productivity. The glutathione S-transferase (GST) family comprises important detoxifying enzymes, which play major roles in biotic and abiotic stress responses by reducing the oxidative damage caused by reactive oxygen species. Pumpkins (Cucurbita maxima) are widely grown, economically important, and nutritious; however, their yield can be severely affected by cold stress. The identification of putative candidate genes responsible for cold-stress tolerance, including the GST family genes, is therefore vital. For the first time, we identified 32 C. maxima GST (CmaGST) genes using a combination of bioinformatics approaches and characterized them by expression profiling. These CmaGST genes represent seven of the 14 known classes of plant GSTs, with 18 CmaGSTs categorized into the tau class. The CmaGSTs were distributed across 13 of pumpkin’s 20 chromosomes, with the highest numbers found on chromosomes 4 and 6. The large number of CmaGST genes resulted from gene duplication; 11 and 5 pairs of CmaGST genes were segmental- and tandem-duplicated, respectively. In addition, all CmaGST genes showed organ-specific expression. The expression of the putative GST genes in pumpkin was examined under cold stress in two lines with contrasting cold tolerance: cold-tolerant CP-1 (C. maxima) and cold-susceptible EP-1 (Cucurbita moschata). Seven genes (CmaGSTU3, CmaGSTU7, CmaGSTU8, CmaGSTU9, CmaGSTU11, CmaGSTU12, and CmaGSTU14) were highly expressed in the cold-tolerant line and are putative candidates for use in breeding cold-tolerant crop varieties. These results increase our understanding of the cold-stress-related functions of the GST family, as well as potentially enhancing pumpkin breeding programs.

Description of a New Allergenic Member of the Glutathione Transferase (GST) Family from Ascaris with Omega-Class Features

Description of a New Allergenic Member of the Glutathione Transferase (GST) Family from Ascaris with Omega-Class Features

Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis.

Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.

High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.

Glutathione S-transferase (GST) family members promote carcinogenesis and cancer progression. We assessed GST pi 1 (GSTP1) mRNA and protein levels in hepatocellular carcinoma (HCC) using genome databases and tissue microarray (TMA) technology. We found that in cancerous tissues, GSTP1 mRNA was down-regulated in genome databases, and immunohistochemical staining of GSTP1 in 237 HCC cases varied from negative to strongly positive. GSTP1 levels correlated negatively with tumor size and serum alpha-fetoprotein (AFP) in HCC patients, and higher GSTP1 levels associated with longer overall survival (OS) and disease-free survival (DFS). We also found that GSTP1 overexpression restrained HepG2 and Huh7 liver cancer cell proliferation in vivo and in vitro. GSTP1 arrested the cell cycle at G1/S by up-regulating p21 and p27 and down-regulating p-Akt. Interrupting GSTP1 gene expression promoted liver cancer cell proliferation and increased the percentage of cells in S phase by decreasing levels of p21 and p27 and increasing p-Akt. These results suggest high GSTP1 levels provide a better prognosis through suppression of tumorigenesis in HCC.

Genome-wide identification and expression analysis of glutathione S-transferase gene family in tomato: Gaining an insight to their physiological and stress-specific roles.

Glutathione S-transferase (GST) refers to one of the major detoxifying enzymes that plays an important role in different abiotic and biotic stress modulation pathways of plant. The present study aimed to a comprehensive genome-wide functional characterization of GST genes and proteins in tomato (Solanum lycopersicum L.). The whole genome sequence analysis revealed the presence of 90 GST genes in tomato, the largest GST gene family reported till date. Eight segmental duplicated gene pairs might contribute significantly to the expansion of SlGST gene family. Based on phylogenetic analysis of tomato, rice, and Arabidopsis GST proteins, GST family members could be further divided into ten classes. Members of each orthologous class showed high conservancy among themselves. Tau and lambda are the major classes of tomato; while tau and phi are the major classes for rice and Arabidopsis. Chromosomal localization revealed highly uneven distribution of SlGST genes in 13 different chromosomes, where chromosome 9 possessed the highest number of genes. Based on publicly available microarray data, expression analysis of 30 available SlGST genes exhibited a differential pattern in all the analyzed tissues and developmental stages. Moreover, most of the members showed highly induced expression in response to multiple biotic and abiotic stress inducers that could be harmonized with the increase in total GST enzyme activity under several stress conditions. Activity of tomato GST could be enhanced further by using some positive modulators (safeners) that have been predicted through molecular docking of SlGSTU5 and ligands. Moreover, tomato GST proteins are predicted to interact with a lot of other glutathione synthesizing and utilizing enzymes such as glutathione peroxidase, glutathione reductase, glutathione synthetase and γ-glutamyltransferase. This comprehensive genome-wide analysis and expression profiling would provide a rational platform and possibility to explore the versatile role of GST genes in crop engineering.