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)

The glutathione transferase mu gene (GST1) and the debrisoquine hydroxylase gene (CYP2D6) are known to be polymorphic in the human population and have been associated with increased susceptibility to cancer. Smokers with low lymphocyte GST mu activity are at higher risk for lung cancer, while low debrisoquine hydroxylase activity has been correlated with lower risk for lung and bladder cancer. Phenotypic characterization of these polymorphisms by lymphocyte enzyme activity (GST) and urine metabolite ratios (debrisoquine) is cumbersome for population studies. Recent cloning and sequencing of the mutant alleles of these genes has allowed genotyping via the polymerase chain reaction (PCR). Advantages of PCR approaches are speed, technical simplicity, and minimal sample requirements. This article reviews the PCR-based methods for detection of genetic polymorphisms in human cancer susceptibility genes.
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PMID:Detection of DNA sequence polymorphisms in carcinogen metabolism genes by polymerase chain reaction. 168 53

Cancer development is a long-term multistep process which allows interventional measure before the clinical disease emerges. The detection of natural substances which can block the process of carcinogenesis is as important as the identification of anti-tumoral drugs since they might be used in chemoprevention of cancer in high-risk groups. In vivo rodent models of chemical carcinogenesis have been used to study plant-derived inhibitors of carcinogenesis such as indoles, coumarins, isothiocyanates, flavones, phenols and allyl-sulfides. Since the standard in vivo rodent bioassay is prolonged and expensive, shorter reliable protocols are needed. Two in vivo medium-term protocols for evaluation of modifiers of carcinogenesis are presented, one related to liver and the other to bladder cancer. Both protocols use rats, last 8 and 36 weeks and are based on the two-step concept of carcinogenesis: initiation and promotion. The protocols use respectively the development of altered foci of hepatocytes expressing immunohistochemically the placental form of glutathione S-transferase and the appearance of pre-neoplastic urothelium and papillomas as the "end-points". The use of these protocols for detection of plant-derived inhibitors of carcinogenesis appear warranted.
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PMID:Medium-term protocols for in vivo evaluation of chemical modifiers of carcinogenesis. 184 12

The antischistosomal agent oltipraz displays a unique ability to inhibit chemically induced carcinogenesis in a variety of animal models. Its apparent lack of carcinogen specificity and low toxicity make it an attractive candidate for further development as a chemopreventive agent. The mechanism by which oltipraz affords cellular protection is thought to involve the modulation of phase II detoxication enzymes. The present study examines the regulation of each class of glutathione S-transferase (EC 2.5.1.18) in mice after a single oral administration of oltipraz. Glutathione S-transferase activity in the liver increased in a dose-dependent manner after drug exposure. Oltipraz administration (1 g/kg, by gavage) elevated glutathione S-transferase activity to a maximum (4.5-fold) on day 4 after treatment. Western blot analyses demonstrated the induction of all three classes of glutathione S-transferase (alpha, mu, and pi) by oltipraz. Our murine studies suggest that the chemopreventive activity of oltipraz may be due in part to its ability to elevate glutathione S-transferase-mu activity. Consistent with this possibility, associations between the glutathione S-transferase-mu-null phenotype and increased risk for lung, larynx, and bladder cancer have been recently demonstrated in humans. Coordinate elevations in enzymatic activity were preceded by significant elevations in glutathione S-transferase alpha, mu, and pi RNA on day 2 after treatment. Although nuclear run-on assays confirmed the transcriptional induction of all three classes, the maintenance of elevations in enzymatic activity after RNA levels returned to base-line suggests that additional mechanisms are required to regulate glutathione S-transferase expression. Preclinical findings are presented that characterize the response of each class of glutathione S-transferase to oltipraz exposure and support the use of these enzymes as intermediate markers of the chemopreventive activity of oltipraz.
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PMID:Coordinate induction of glutathione S-transferase alpha, mu, and pi expression in murine liver after a single administration of oltipraz. 751 79

Up to 90% of all cancers are possibly caused by environmental factors, such as tobacco smoke, diet and occupational exposures. The majority of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. The xenobiotic-metabolising machinery contains two main types of enzymes: the phase-I cytochromes P-450 (CYP) mediating oxidative metabolism, and phase-II conjugating enzymes. Several phase-I and phase-II genes have recently been cloned and identified in humans. Many of them show polymorphism and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in the CYP subfamilies CYP1A1, CYP2D6 and CYP2E1 have been associated with tobacco smoke-induced lung cancer and other cancers. Defective glutathione S-transferase (GST) and N-acetyltransferase (NAT) enzymes have been associated with an increased risk of developing lung and bladder cancer. There are also several studies in each category in which no associations have been found. The risk of developing lung cancer is dramatically (up to 40-fold) elevated in subpopulations having simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are several difficulties in this area of research. First, many of the observed restriction-fragment length polymorphisms (RFLPs) are due to mutations in introns or other silent areas of DNA, raising the possibility that any associations found between RFLPs and cancer occur only by chance. Second, biologically plausible mechanisms linking genotypes and cancer are lacking in most of the observed cases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility--a review. 760 65

Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase MI (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYP1A1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations.
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PMID:Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility. 769 86

Polycyclic aromatic hydrocarbons, found in cigarette smoke, food and industrial materials, are potential human carcinogens. Deficiency of detoxifying enzymes, such as glutathione transferases, may affect the metabolic fates of these chemicals and raise cancer risks in exposed individuals. The GSTM1 null genotype is a common form of glutathione transferase deficiency. Because knowledge of its ethnic distribution would be useful in epidemiologic studies, we measured the frequencies of the GSTM1 null genotype among healthy blacks, whites, Asian Indians, Chinese, Japanese, Koreans, Filipinos, Samoans and Hispanics. Rapid genotyping was done by use of a PCR assay, with dried blood spots on blotter paper as DNA templates. The frequency of the null genotype ranged from 0.31 among blacks to 0.88 among Samoans. The PCR assay was also applied to a pilot study of 114 bladder cancer cases from Kaiser Permanente Medical Center, Harbor City, California. DNA for these cases was obtained from paraffin-embedded surgical specimens. The overall odds ratio for bladder cancer with the GSTM1 null genotype was 1.4 (95% confidence interval 0.94-2.1), indicating no statistical difference in null genotype frequencies among bladder cancer patients compared to a healthy population. Large epidemiologic studies, which can be accomplished with dried blood spots or paraffin-embedded tissue specimens, may be useful for further assessment.
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PMID:Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibility. 820 72

We examined the genotypes of two polymorphic genes involved in the detoxification of several mutagenic and carcinogenic compounds in relation to tobacco smoking-associated urinary mutagenicity. The genes studied were the glutathione S-transferase-encoding GSTM1 gene and acetyltransferase-encoding NAT2 gene. Smokers with no GSTM1 gene (n = 7) had urine that was several times more mutagenic than that of smokers with the gene (n = 10). The mean level of urinary mutagenicity in presence of metabolic activation was 2527 +/- 958 revertants/100 ml urine for GSTM1-smokers compared to 766 +/- 560 revertants/100 ml for GSTM1+ smokers (P < 0.001) using the bacterial strain YG1024. The corresponding values using the TA98 strain were 336 +/- 124 and 123 +/- 75 (P < 0.001). In contrast, we failed to show any difference in the level of urinary mutagenicity between slow-acetylator and fast-acetylator NAT2 genotypes among smokers (n = 17) or non-smokers (n = 35). Our results offer one explanation for the recent findings that GSTM1 polymorphism is a risk modifier in smoking-related cancers, especially bladder cancer.
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PMID:Modulation of urinary mutagenicity by genetically determined carcinogen metabolism in smokers. 820 80

Enzyme-linked immunoassays (ELISAs) based on the double-antibody sandwich technique have been developed for the quantitative analysis of the major human cytosolic class Pi, Mu and Alpha glutathione transferases (GSTs). The procedures were optimized with respect to antibody concentration for coating of plates as well as other parameters in order to achieve high sensitivity and accuracy. No cross-reactivity was detected between members of the three different classes of GSTs or among the Mu class GSTs M2-2, M3-3 and M4-4 with the ELISA for GST M1-1. The ELISAs have been applied to establish the cytosolic GST profiles of 10 cell lines and to monitor the plasma GST levels in cancer patients. The results revealed that the class Pi GST was the dominant isoenzyme in six (LS 174T, HCT-8, Hu 549 Pat, K-562, U-937 and Hu 549) out of nine tumor cell lines and immortalized hepatocytes (Chang Liver). The isoenzymes A1-1 and M1-1 were determined to be the major GST components in Hep G2 and HeLa cells, respectively. In a clinical study, the majority of the patients with urinary bladder cancer were found to have increased plasma levels of both GST A1-1 and GST P1-1 (10/15), while patients with renal cancer frequently showed increases only in GST P1-1 (5/8). The results demonstrate that the ELISAs are suitable for analyzing GST phenotypes in both normal and tumor cells and in monitoring plasma levels of GSTs in cancer patients.
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PMID:Isoenzyme-specific quantitative immunoassays for cytosolic glutathione transferases and measurement of the enzymes in blood plasma from cancer patients and in tumor cell lines. 828 Jul 91

In this study, we have examined the relationship between sensitivity to mitomycin C (MMC) and glutathione (GSH) and glutathione transferase (GST) levels using a panel of three unrelated human bladder cancer cell lines. J82, HT-1197, and SCaBER. Cell lines HT-1197 and SCaBER were about 2- and 4.5-fold more resistant to MMC as compared to J82. Although the GSH level did not differ significantly in these cell lines, GST activity in HT-1197 and SCaBER cells were higher by about 2.3- and 6.0-fold, respectively, as compared to J82. Similar to GST activity, GST pi content was highest in the most insensitive cell line and lowest in J82 cells. The cytotoxicity of MMC was increased significantly in these cells by a 1-h pretreatment with a nontoxic concentration of ethacrynic acid (EA), an inhibitor of GST activity. EA pretreatment resulted in a marked GSH depletion as well as GST activity inhibition in both of these cells. Although pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused similar GSH depletion, the cytotoxicity of MMC was enhanced only in SCaBER cells. The differential effect of BSO on MMC cytotoxicity in these cell lines appeared to be due to the differences in the extent of GSH regeneration after removal of BSO. While a marked GSH regeneration occurred in J82 cells within 1 h after BSO removal, such an effect was not observed in SCaBER cells. Combined treatment of these cells with BSO and EA produced a greater potentiation of MMC cytotoxicity in both the cell lines when compared to BSO or EA treatment alone. We conclude that GSH/GST levels may affect the sensitivity of human bladder cancer cells to MMC.
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PMID:Mitomycin C sensitivity in human bladder cancer cells: possible role of glutathione and glutathione transferase in resistance. 831 48

The isoenzyme mu of glutathione S-transferase (GST mu) is dominantly inherited and the prevalence of this isoenzyme in the population is about 60%. An increased risk of lung cancer has been previously shown among smokers lacking GST mu in (Seidegard J., Pero R.W., Miller D.G., Beattie E.J. (1986) Carcinogenesis, 7, 751-753). The frequency of the phenotypes of this isoenzyme in bladder cancer patients (n = 75), in larynx cancer patients (n = 78) and healthy controls matched for age and smoking history is reported here. A significantly higher proportion of smokers in the control group had measurable GST mu compared with bladder cancer patients (54.6% vs. 33.3%, P < 0.01) and also compared to larynx cancer patients (55.1% vs. 33.3%, P < 0.01). Odds ratio analysis indicates that smokers with this polymorphic variant have an approximately 2-fold greater risk of developing these cancers.
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PMID:Human glutathione S-transferase mu (GST mu) deficiency as a marker for the susceptibility to bladder and larynx cancer among smokers. 842 49


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