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)

Multiple allelism at loci encoding detoxicating enzymes is associated with cancer risk. We have studied genetic variation at the glutathione S-transferase GSTM1 locus to see whether phenotypes confer altered susceptibility to basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), or multiple skin tumours of different histological types. The frequency of GSTM1 null in cases and controls (52%) was similar, except for patients with two or more tumours of different types (71%, p = 0.033). GSTM1 A/B was reduced in frequency (p < 0.05) in patients with single or multiple BCC. Thus GSTM1 A/B may be protective, and effectiveness of detoxication may be a factor determining susceptibility to skin cancer.
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PMID:Glutathione S-transferase GSTM1 phenotypes and protection against cutaneous tumours. 790 99

The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.
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PMID:Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender. 855 81

The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has been investigated. We have reported previously two GSTM3 alleles, GSTM3*A and GSTM3*B, distinguished by a recognition motif for the YY1 transcription factor in GSTM3*B. In this study, immunohistochemistry was used to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3*A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BB genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. Genotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 loci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, and CYP1A1 genotypes in the cases and controls were not different. Dividing the BCC cases into groups of 92 patients with 1 lesion and 194 patients with 2-35 lesions showed that the frequencies of GSTM3 BB (2.6%) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost significantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601, chi 2(1) = 3.390; 6.5%, exact P = 0.055, chi 2(1) = 4.946, respectively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with increasing numbers of tumors. This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively). The data suggest that, like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increased tumor numbers, it appears that YY1 acts as an activator of the recognition motif in GSTM3*B.
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PMID:Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma. 861 34

Basal cell carcinoma (BCC) places increasing burdens on clinicians; incidence is rising and patients may develop multiple primary tumors. Although UV exposure is critical, many patients develop tumors at less-exposed sites, such as the trunk, suggesting a genetic predisposition. We previously showed that polymorphism in loci encoding the detoxifying enzymes, glutathione S-transferase (GSTM1, GSTM3, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) influences susceptibility to BCC. We now describe a case-control approach in 345 patients with BCC that examines the role of these polymorphisms and patient characteristics (age, gender, skin type, hair color, eye color, smoking, occupation) in determining susceptibility to truncal tumors. GST and CYP genotypes were identified using polymerase chain reaction-based methods. Patients with one or more truncal tumors were significantly younger (p = 0.0170) than those with no truncal tumors. Male gender also appeared more common in the truncal tumor group, although this did not achieve significance (p = 0.0925). Patients whose first tumor was truncal had significantly more tumors (p = 0.0297). GSTT1 null (p = 0.0245, odds ratio 2.24) and CYP1A1 Ile/Ile (p = 0.0386, odds ratio 2.86) were associated with truncal site after correction for age and gender. The combination, GSTT1 null and CYP1A1 Ile/Ile, was particularly significant (p = 0.0059, odds ratio = 2.95). These effects were present after correction for tumor numbers. These data show first, patients with truncal tumors constitute a high-risk group for BCC, second, a significant genetic influence on BCC site, and third, a significant interaction between GSTT1 and CYP1A1 genotypes.
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PMID:Truncal tumor site is associated with high risk of multiple basal cell carcinoma and is influenced by glutathione S-transferase, GSTT1, and cytochrome P450, CYP1A1 genotypes, and their interaction. 907 84

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two-factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09-3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.
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PMID:Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of further primary cutaneous basal cell carcinoma. 927 22

Though a developing body of data indicates polymorphism at GST genes influences cancer susceptibility, it is unclear why a genotype is associated with one cancer but not another. We believe the GST exert a critical role in normal cell house-keeping activities. GSTM1, GSTM3 and GSTT1 influence tumorigenesis because these enzymes utilise the products of UV-induced oxidative stress. Further support for the importance of these genes in the protection of skin from UV comes from studies in systemic lupus erythematosus (Ollier et al, 1996). Thus, GSTM1 null is associated with increased anti-Ro (but not anti-La) antibodies, a phenotype associated with photosensitivity. At present there is no basis for predicting which cancers will be influenced by GST polymorphisms though other studies do indicate that the GSTs are critical in the metabolism of environmental carcinogens. For example, GSTT1 null confers an increased risk of astrocytoma (Hand et al, 1996). While brain tumours are not clearly associated with environmental pollutants, N-methyl-N-nitrosourea, processed meats and occupation have been implicated. Why GSTT1 but not GSTM1 or GSTM3 influences the risk of astrocytoma is unclear. GSTM3 appears a good susceptibility candidate, as some astrocytes demonstrate strong expression (Hand et al, 1996). Susceptibility to squamous cell cancer of the larynx, a pathology associated with chronic consumption of tobacco and alcohol, is also influenced by allelism at GSTM3 (Jahnke et al, 1996). The roles of CYP2D6 and CYP1A1 are even more unclear, though the finding that systemic agents such as arsenic predispose to multiple BCC, suggests that CYP2D6-mediated hepatic detoxification of photosensitizing agents may be important. Importantly, the extent of altered risk conferred by genotypes is generally 2-3 fold and it is necessary to identify which other genes interact with the GST so that haplotypes associated with 10-20 fold increases in risk can be defined.
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PMID:Polymorphism in glutathione S-transferase loci as a risk factor for common cancers. 944 13

The glutathione S-transferase supergene family includes several loci that demonstrate well characterised polymorphisms. The apparently critical role of these enzymes in cellular protection from the cytotoxic and mutagenic effects of electrophiles suggest that alleles associated with impaired detoxification will confer an increased susceptibility to a wide range of diseases. This hypothesis has been examined in case control studies and while data in some diseases such as lung cancer are conflicting, an increasing body of evidence suggests the importance of several glutathione S-transferase polymorphisms. In particular, GST genotypes have been associated with an increased susceptibility or worse outcome in diseases associated with oxidative stress. For example, both GSTM1 and GSTT1 genotypes are associated with susceptibility and outcome in cutaneous basal cell carcinoma. It still remains unclear however, why particular glutathione S-transferase loci are associated with altered risk in some diseases but not others. Further, the true in vivo substrates of these enzymes is unknown, consequently their mechanism of action remains unclear.
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PMID:Glutathione S-transferase polymorphisms: influence on susceptibility to cancer. 967 66

We previously reported associations between numbers of basal cell carcinomas (BCCs) and glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P450 (CYP2D6) genotypes. Thus, although GSTM1 AB is protective, GSTM1 null, GSTT1 null, and CYP2D6 EM are associated with increased numbers of lesions. Here, we examine the hypothesis that these genotypes are associated with high-risk subgroups. The subgroup studied comprised 119 patients with more than one previously unidentified BCC at first or later presentations [multiple presentation phenotype (MPP)]. These patients were part of a group of 773 BCC patients that also included 567 patients with one BCC and 87 patients with only one lesion at each presentation [single presentation phenotype (SPP)] but who developed multiple BCCs. The number of tumors in the MPP was significantly greater than that in the SPP groups. In the MPP but not SPP patients, GSTM1 AB, GSTT1 null, and CYP2D6 EM were significantly associated with BCC numbers, suggesting that previously observed associations reflect the influence of these genes only in the MPP cases. There was no evidence that MPP patients had received more UV exposure. We also determined whether the increased numbers of BCC in the MPP cases reflects an association with the truncal tumor phenotype. The values of the rate ratios indicated that the MPP is a marker for the risk of many BCCs, although the combination of MPP and a truncal tumor is a higher-risk phenotype. The data demonstrate the heterogeneity in BCC patients, which reflects differences in genetic factors that determine skin response to UV.
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PMID:Presentation with multiple cutaneous basal cell carcinomas: association of glutathione S-transferase and cytochrome P450 genotypes with clinical phenotype. 995 Feb 41

The glutathione S-transferase supergene family is an important part of cellular enzymic defence against endogenous and exogenous chemicals, many of which have a carcinogenic potential. However, while a wide variety of chemicals can act as substrates for different members of the supergene family, the precise function of these enzymes remains unclear. The supergene family comprises several gene families that include polymorphic loci, prompting the hypothesis that allelic variants associated with less effective detoxification of potential carcinogens can confer an increased susceptibility to cancer. For example, the null genotypes at the mu class GSTM1 and theta class GSTT1 loci have attracted particular interest, and recently identified allelic variants at the mu class GSTM3 and pi class GSTP1 loci are also putative susceptibility candidates. However, while associations between GSTM1 and GSTT1 genotypes and risk have been observed in some case-control studies in lung, bladder and colon cancers, other studies have reported contrary findings, and the importance of these polymorphisms in mediating the risk of smoking-related cancers remains generally unproven. We describe the influence of glutathione S-transferase polymorphisms on the risk of several cancers, including basal cell carcinoma of skin. In the latter cancer, associations between tumour numbers, site and accrual have been observed, suggesting a role for GST enzymes in the detoxification of the products of ultraviolet radiation-induced oxidative stress. We review below current knowledge of polymorphism in GST loci, possible in vivo GST substrates, and the difficulties of determining the role of this complex gene family on the basis of available epidemiological data.
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PMID:The glutathione S-transferases: influence of polymorphism on cancer susceptibility. 1049 61

Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility.
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PMID:Glutathione S-transferase polymorphisms and their biological consequences. 1097 Dec 1


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