Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 chemiluminescence 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 CumOOH. Our results indicate that erythrocytes from individuals with GSTT1 null genotype are not abnormally susceptible to CumOOH-induced oxidant challenge.
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PMID:Are individuals with glutathione S-transferase GSTT1 null genotype more susceptible to in vitro oxidative damage? 1068 Oct 96

Aflatoxins together with chronic hepatitis B virus (HBV) infection contribute to the high incidence of hepatocellular carcinoma in developing countries. An understanding of the mechanism of interaction between these factors would provide a strong rationale for developing effective prevention strategies. In this study in The Gambia we examined the effect of environmental (place of residence and timing of sample collection) and host factors (age, sex, HBV status and interindividual variations in carcinogen metabolising enzymes) in determining blood aflatoxin-albumin adduct levels in 357 individuals of whom 181 were chronic HBV carriers. Samples were analysed for aflatoxin-albumin adducts, HBV status and genotypes of glutathione S-transferase (GST) M1, GSTT1, GSTP1 and epoxide hydrolase (EPXH). Urine samples were analysed for 6beta-hydroxycortisol:cortisol ratio as a marker of cytochrome P450 (CYP) 3A4 activity. Adduct levels were significantly higher in subjects resident in rural [geometric mean adduct level 34.9 pg aflatoxin B1-lysine equivalent (28.5-42.8; 95%CI)/mg albumin] than in periurban areas [22.2 pg (14.9-33.4)/mg] and were approximately twice as high in the dry season [mid-February to March; 83.2 pg (53.3-130.8)/mg] than the wet [July to August; 34.9 pg (28.5-42.8)/mg]. In contrast, HBV status, CYP3A4 phenotype, GSTT1, GSTP1 and EPXH genotypes were not associated with aflatoxin-albumin adduct level. However, mean adduct levels were significantly higher in non-HBV infected subjects with GSTM1 null genotype. The main factors which affect aflatoxin-albumin adduct levels in this population are environmental, notably place of residence and timing of sample collection. This study further emphasises the priority to reduce aflatoxin exposure in these communities by primary prevention measures.
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PMID:Environmental and genetic determinants of aflatoxin-albumin adducts in the Gambia. 1072 87

The glutathione S-transferase (GST) family of enzymes function in the body to detoxify carcinogenic compounds. Several genes that code for these enzymes are polymorphic, with particular genotypes previously shown to confer an increased cancer risk. In this study, we investigated the role of three GST genes (GSTM1, GSTP1 and GSTT1) in the development of sporadic breast cancer. Genotypes were determined in 129 breast cancer affected and 129 age and sex matched control individuals. Results did not support an involvement of these specific GST gene polymorphisms, either independently or in combination, in susceptibility to sporadic breast cancer in the tested Australian Caucasian population.
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PMID:Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and breast cancer susceptibility. 1077 39

Numerous specific genetic polymorphisms (PM) in the multi-gene families of cytochromes P450 (CYPs) and glutathione S-transferases (GSTs) have been described in the human population in the past decade. For example, one or more PM have been identified in human CYP1A1, CYP1B1, CYP2C9, CYP2C18, CYP2D6, and CYP2E1. Recent studies using cDNA expressed human CYPs have suggested that CYP3A4 is the principal human CYP involved in the oxidation of parathion and probably other organo(thio)phosphate (OP) insecticides and thus PM in this CYP might influence susceptibility to OP. However, although large (> 10-fold) variability in CYP3A4 activity in human liver has been found, thus far no genetic basis for differences in activity or expression of CYP3A4 have been identified. Three GSTs are also polymorphic in the human population. Approximately 50% of the Caucasian population are homozygous for a gene deletion of the mu class GSTM1, and approximately 20% of Caucasians and over 60% of certain Asian populations are homozygous for a partial deletion of the theta-class GSTT1. Recently, several single nucleotide polymorphisms in human GSTP1 have also been described, and have altered activity toward several substrates. No studies have yet determined the relative activities of human GSTM1, T1 or PI towards methylparathion or other pesticides, and thus the potential significance of the common polymorphisms of these genes on pesticide susceptibility is unknown. Numerous studies have demonstrated that resistance of a variety of insects to several different insecticides, including DDT, has been attributed to the overexpression of theta-class GSTs as well as certain CYPs. Thus, it remains possible that genetic PM in human GSTs and/or CYP enzymes could increase or decrease sensitivity to certain pesticides. Few epidemiological studies have examined whether any of the known CYP or GST PMs are associated with adverse outcomes in populations occupationally-exposed to pesticides.
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PMID:Biotransformation enzyme polymorphism and pesticide susceptibility. 1079 90

Renal cell carcinoma (RCC) has known environmental risk factors, notably smoking, and enzymes that biotransform carcinogens have high levels of activity in the kidney. However, a possible role of polymorphisms in these enzymes in RCC etiology has received little study. We investigated glutathione S-transferase (GST) polymorphisms in a population-based case-control study of RCC. Subjects completed a structured interview, and DNA was isolated from pathological material or buccal cells for 130 cases, and from blood for 505 controls. Genotypes for GSTM1 and GSTT1 were determined by multiplex PCR, and for GSTP1 by oligonucleotide ligation assay. The frequency of GSTM1 null genotype was 50.0% in cases and 50.5% in controls, with an adjusted odds ratio (OR) of 1.0 [95% confidence interval (CI), 0.6-1.6]. For GSTP1, the frequencies of genotypes AA, AG, and GG representing the Ile104Val variant were: cases, 44.6%, 43.1%, and 12.3%; controls, 43.4%, 44.0%, and 12.6%; OR for AG and GG, 1.0 (95% CI, 0.6-1.6). An excess of the GSTT1 null genotype was observed in cases compared with controls, 28.6% versus 18.5% (OR, 1.9; 95% CI, 1.1-3.4). The association with GSTT1 was present among both smokers and nonsmokers, but was modified by body mass index, a recognized risk factor for RCC; among subjects in the lowest tertile of body mass index, the OR for GSTT1 null was 4.8 (95% CI, 1.8-13.0). The association between GSTT1 null and increased RCC risk in this population-based study suggests that activity of the GSTT1 enzyme protects against RCC. This contrasts with a recent report of reduced risk of RCC associated with GSTT1 null in a cohort of trichloroethene-exposed workers and suggests that specific chemical exposures alter the effect of GSTT1 on cancer risk.
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PMID:Glutathione S-transferase M1, T1, and P1 polymorphisms as risk factors for renal cell carcinoma: a case-control study. 1079 92

Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), N-acetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.
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PMID:Polymorphism of drug-metabolizing enzymes in relation to individual susceptibility to industrial chemicals. 1081 37

Individuals with a homozygous deletion of the glutathione S-transferase theta 1 (GSTT1) gene lack GSTT1 enzymatic detoxification of environmental carcinogens by conjugation with glutathione. The GSTT1 gene deletion has been associated with carcinogen-induced chromosomal changes in lymphocytes, and some but not all epidemiological evidence has suggested that the GSTT1 gene deletion may increase susceptibility to myelodysplasia. We conducted a case-control study to test whether individuals with an inherited homozygous deletion of the GSTT1 gene are at increased risk of acute myeloid leukemia (AML). The GSTT1 and GST mu 1 (GSTM1) genotypes were determined by PCR using lymphocyte or bone marrow DNA from 297 AML patients and 152 controls. AML patients were selected from Southwest Oncology Group clinical studies, and controls were identified by random digit dialing in Washington state. No association was observed between the GSTT1 gene deletion and AML [race-adjusted odds ratio (OR), 0.94; 95% confidence interval (CI), 0.55-1.60] or between the GSTM1 gene deletion and AML (race-adjusted OR, 1.26; 95% CI, 0.85-1.88). Patients with secondary AML had a slightly higher prevalence of the GSTT1 and GSTM1 gene deletions compared with de novo AML patients or controls, but this was consistent with chance. Exploratory analyses of AML cytogenetics suggested a few associations, i.e., between the GSTT1 gene deletion and trisomy 8, and between the GSTM1 gene deletion and non-8 trisomies or inv(16). These results do not support the hypothesis that the GSTT1 gene deletion is related to the incidence of AML.
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PMID:Glutathione S-transferase theta 1 gene deletion and risk of acute myeloid leukemia. 1081 89

GSTM1 and GSTT1 are polymorphic genes. Absence of enzyme activity is due to homozygous inherited deletion of the gene, reducing detoxification of carcinogens such as epoxides and alkylating agents and potentially increasing cancer risk. We hypothesized that GST null genotype would increase risk of acute myeloid leukemia and myelodysplasia (AML/MDS) in children. DNA was extracted from bone marrow slides of 292 AML/MDS patients. PCR amplification was used to assign GSTM1 and GSTT1 genotypes for cases and controls. Given that the frequency of the null genotype varies by ethnicity and that the majority of the cases were Caucasian, analyses were restricted to 232 white (non-Hispanic) cases and 153 Caucasian non cancer controls. The frequency of GSTM1 null was significantly increased in AML/MDS cases compared with controls [64 versus 47%; odds ratio (OR), 2.0 [95% confidence interval (CI), 1.3-3.1]; P = 0.001], whereas the frequency of GSTT1 null genotype in AML/MDS cases was not statistically different from controls. AML comprises biologically distinct subtypes, and a test for homogeneity revealed a statistically significant difference among subtypes (P = 0.04; df, 8) for GSTM1 only. In particular, there was an increased frequency of GSTM1 null genotypes in French-American-British groups M3 [82%; n = 22; OR, 5.1 (95% CI, 1.6-21.3)] and M4 [72%; n = 53; OR, 2.9 (95% CI, 1.4-6.0)]. We conclude that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French-American-British groups M3 and M4. This may indicate an important role for exogenous carcinogens in the etiology of childhood AML.
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PMID:Glutathione S-transferase polymorphisms in children with myeloid leukemia: a Children's Cancer Group study. 1086 89

We examined associations for glutathione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) genotypes and breast cancer in the Carolina Breast Cancer Study, a population-based, case-control study in North Carolina. Odds ratios were close to the null value for each GST locus among African-American women (278 cases and 271 controls) and white women (410 cases and 392 controls), as well as pre- and postmenopausal women. For women with a history of breast cancer in one or more first-degree relatives, odds ratios were 2.1 (95% confidence interval, 1.0-4.2) for GSTM1 null and 1.9 (0.8-4.6) for GSTT1 null genotypes. Among women with a family history, age at diagnosis was significantly earlier for those with the GSTM1 null genotype. We did not observe strong evidence for modification of odds ratios for smoking according to GST genotypes. There was no evidence for combined effects of GSTM1, GSTT1, and GSTP1 genotypes, and there were no combined effects for GST genotypes and the catechol O-methyltransferase genotype. We conclude that GSTM1, GSTT1, and GSTP1 genotypes do not play a strong role in susceptibility to breast cancer. However, the role of GST genotypes in age at onset and risk of breast cancer among women with a family history merits further investigation.
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PMID:Glutathione S-transferases M1, T1, and P1 and breast cancer. 1086 90

The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons. This risk may be modified by variation in metabolism genes, including GSTM1, which encodes an enzyme known to detoxify polycyclic aromatic hydrocarbons. To investigate the relationship between GST genotypes and lung cancer risk in Xuan Wei County, we analyzed GSTM1 and GSTT1 genotypes in a population-based case-control study. A total of 122 lung cancer patients and 122 controls, individually matched by age, sex, and home fuel type, were studied. Compared to subjects who used less than 130 tons of smoky coal during their lifetime, heavier users (> or =130 tons) had a 2.4-fold (95% confidence interval, 1.3-4.4) increased risk of lung cancer. The GSTM1-null genotype was associated with a 2.3-fold (95% confidence interval, 1.3-4.2) increased risk of lung cancer. Furthermore, there was some evidence that smoky coal use was more strongly associated with lung cancer risk among GSTM1-null versus GSTM1-positive individuals. In contrast, the GSTT1 genotype was not significantly associated with lung cancer risk. Our data suggest that the GSTM1-null genotype may enhance susceptibility to air pollution from indoor coal combustion emissions.
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PMID:Indoor coal combustion emissions, GSTM1 and GSTT1 genotypes, and lung cancer risk: a case-control study in Xuan Wei, China. 1086 96


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