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)

We have studied the mutant frequency in the human gene for hypoxanthine-guanine phosphoribosyl transferase (hprt) using the T-cell cloning assay, the aromatic DNA adduct level using the 32P-postlabelling assay, and related the levels of these biomarkers to the genotypes for glutathione transferase (GST mu) and N-acetyltransferase (NAT2) in non-smoking bus maintenance workers exposed to diesel exhaust. No difference in mutant frequency was observed between the 47 exposed (8.6 x 10(-6), age range 27-65) and the 22 control individuals (8.4 x 10(-6), age range 23-61), while the difference in adduct level (3.2 versus 2.3 x 10(-8)) was highly significant (P = 0.0009). Both mutant frequency and adduct level were highest in the 16 most heavily exposed workers. Overall, a significant increase of mutant frequency was observed with adduct level (P = 0.008) as well as with age (P < 0.0001). The age dependence was higher in the GSTM1-negative slow acetylators (3.1%/year) as compared to the three other genotype combinations (2.4-2.5%/year). There was no significant difference in mutant frequency or in adduct level between the GSTM1-negative (49.3% of the population) and positive individuals, or between the slow (60.9% of the population) and rapid acetylators. Among the slow acetylators, however, a significantly higher adduct level (P = 0.03) was obtained for the GSTM1-negative individuals as compared to the GSTM1-positive individuals. These results suggest a possible role of both GST mu and NAT2 for individual susceptibility to carcinogen exposure.
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PMID:Relationship between hprt mutant frequency, aromatic DNA adducts and genotypes for GSTM1 and NAT2 in bus maintenance workers. 754 77

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

Studies of mutation at the hypoxanthine phosphoribosyl transferase (hrpt) locus in human T-cells have the potential to elucidate the molecular basis of in vivo mutagenesis, reveal exposure dependent changes in ther background frequency of mutation, and provide knowledge on individual sensitivity. Styrene exposed lamination workers in Bohemia showed a significantly higher frequency of hprt mutant cells than Swedish control populations studied simultaneously. In a study of 47 healthy, non-smoking male bus maintenance workers exposed to diesel exhausts, soot and oil, and 22 unexposed controls, a significant correlation (P = 0.008) was obtained between the levels of aromatic DNA adducts and frequencies of hprt-mutant T-cells. In the group of workers with the highest exposure, subjects with glutathione S-transferase (GSTM1) deficiency showed significantly higher (P < 0.05) frequency of hprt mutant T-cells than GSTM1-positive subjects. The highest adduct levels were found in subjects with the combined genotype of GSTM1 and NAT2 deficiency (GSTM1-negative slow acetylators). These results indicate that GSTM1 and NAT2 genotypes may play a role in determining the individual levels of hprt mutation and DNA adducts. Using PCR-based screening methods, hprt mutations have been classified in 462 T-cell clones from 43 subjects in this study population. Deletions were found in 3% of the mutants, coding errors in 81% and splice mutations in 17%. Transitions and transversions were equally common, and all types of base substitutions were detected.
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PMID:Analysis of mutation at the hprt locus in human T lymphocytes. 859 72

A growing number of human genetic polymorphisms in drug-metabolizing enzymes (DMEs) are being characterized. Some of these have been shown, quite convincingly, to be correlated with risk of toxicity or cancer, whereas others presently remain equivocal. There is good evidence that the correlation is stronger in populations exposed to a variety of environmental procarcinogens; perhaps 30% of DME substrates are able to be metabolically potentiated. Phase I DMEs, most of which represent cytochromes P450, metabolically activate procarcinogens to genotoxic electrophilic intermediates, and Phase II DMEs conjugate the intermediates to water-soluble derivatives, completing the detoxification cycle. It follows that genetic differences in the regulation, expression and activity of genes coding for Phase I and Phase II DMEs would be crucial factors in defining cancer susceptibility and the toxic or carcinogenic power of environmental chemicals. Not all Phase I and Phase II DMEs are implicated in detoxification; previous work from this and from other laboratories has identified candidate Phase I and Phase II genes in which certain alleles are more likely to be associated with cancer susceptibility. In some cases, the allelic frequencies vary dramatically between ethnic groups. In this review, our current knowledge about polymorphisms in the following genes are updated: the aromatic hydrocarbon receptor (AHR), the CYP1A1 structural gene (which encodes aryl hydrocarbon hydroxylase activity), the CYP1A2 structural gene (arylamine oxidations), the CYP2C19 gene (S-mephenytoin 4'-hydroxylase), the CYP2D6 gene (debrisoquine hydroxylase), the CYP2E1 gene (N,N-dimethylnitrosamine N-demethylase), the null mutant for the GSTM1 gene (glutathione transferase mu), and the NAT2 gene (arylamine N-acetyltransferase). If unequivocal biomarkers of genetic susceptibility to cancer and toxicity can be developed successfully, then identification of individuals at increased risk would be very helpful in the fields of public health and preventive medicine.
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PMID:Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. 863 63

Genetic polymorphisms with functional effects occur in many of the genes encoding drug metabolizing enzymes and are an important cause of adverse drug reaction. Recent advances in the understanding of the molecular genetics of drug-metabolizing enzymes, particularly the cytochromes P450, has enabled the molecular basis of several polymorphisms to be elucidated and genotyping assays using the polymerase chain reaction to be developed. Polymorphisms in this category include those in the cytochrome P450 genes CYP2D6, CYP2C19, CYP2A6, CYP2C9 and CYP2E1, the glutathione S-transferase genes GSTM1 and GSTT1 and the N-acetyltransferase gene NAT2. The molecular basis and importance to drug metabolism of the various polymorphisms as well as evidence for the existence of polymorphisms in other genes encoding drug-metabolizing enzymes such as the UDP-glucuronosyltransferases, the sulphotransferases and the methyltransferases are discussed.
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PMID:Molecular basis of polymorphic drug metabolism. 875 Nov 38

We examined the relation between spontaneous abortion and polymorphisms in two genes, glutathione S-transferase (GSTM1) and N-acetyltransferase (NAT2), which are involved in the metabolism of xenobiotics. In a case-control study of 29 women, we found that, among women with the GSTM1 null genotype, the odds ratio (OR) was 3.1 [95% confidence interval (CI) = 1.3-7.0]. There was less evidence of a relation with NAT2 [Mantel-Haenszel adjusted OR (ORMH) = 1.4; 95% CI = 0.45-4.3]. We sought to replicate the GSTM1 finding in an independent case-control study from New York involving 89 cases. We found an inverse association (OR = 0.8; 95% CI = 0.4-2.4). Taken together, these data provide little evidence of an association between GSTM1 or NAT2 genotype and risk of spontaneous abortion.
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PMID:Xenobiotic metabolism genes and the risk of recurrent spontaneous abortion. 883 64

Increased risk of environmentally induced cancer is associated with various types of exposures and host factors, including differences in carcinogen metabolism. Since many carcinogenic compounds require metabolic activation to enable them to react with cellular macromolecules, individual features of carcinogen metabolism may play an essential role in the development of environmental cancer. In this context, cigarette smoking has often been the main type of carcinogenic exposure examined in human studies. Increasing attention has recently been paid to the dose level at which individual susceptibility may be observed. Present studies on increased risk of smoking-related lung cancer associated with phenotypic or genotypic variation of the genes encoding for CYP1A1 or CYP2D6 enzymes are summarized. Similarly, higher risks of lung or bladder cancer seen at various levels of smoking in association with polymorphism of the glutathione S-transferase gene GSTM1 or NAT1 and NAT2 genes involved in N-acetylation are reviewed. Finally, the influence of CYP2E1, GSTM1, or the combined at-risk genotype on the risk of hepatocellular carcinoma in smokers is briefly discussed.
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PMID:Interaction between dose and susceptibility to environmental cancer: a short review. 925 56

In the present study, the possible role of genetic polymorphism of three drug-metabolizing enzymes, debrisoquine/sparteine hydroxylase (CYP2D6), glutathione S-transferase mu (GSTM1), and N-acetyltransferase (NAT2), as a putative genetic component of human longevity, was explored. A total of 817 DNA samples from a centenarian and a control (20-70 years) population was subjected to PCR-coupled RFLP methods. Subjects were genotyped for the CYP2D6*3 (A2637 deletion) and CYP2D6*4 (G1934A transition) alleles, for four mutations of NAT2 [namely, NAT2*5A (C481T), NAT2*6A (G590A), NAT2*7A (G857A), and NAT2*14A (G191A)], and for the presence or absence of GSTM1 gene deletion. No significant difference was found at these three loci between centenarian and control subjects with respect to allelic variant frequencies, genotype distributions or predicted phenotypes deduced from genotype combinations. By comparing the distribution of combined genotypes for the polymorphisms tested at the CYP2D6, NAT2, and GSTM1 loci, none of the predicted phenotypes concerning debrisoquine hydroxylase extensive-metabolizer or poor-metabolizer phenotypes, slow or fast N-acetylation capacities, and active or defective glutathione S-transferase, could be correlated with human longevity, alone or in combination.
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PMID:Lack of association between human longevity and genetic polymorphisms in drug-metabolizing enzymes at the NAT2, GSTM1 and CYP2D6 loci. 965

The human respiratory epithelium is in direct contact with chemical carcinogens and toxins in inhaled air. Therefore, the activities of xenobiotic-metabolising enzymes in this epithelium could modulate respiratory toxicity and carcinogenesis. We determined the expression of several xenobiotic-metabolising enzymes, including phase I and phase II enzymes, in human bronchial mucosa and peripheral lung tissues. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of phase I enzymes showed CYP1A1 and CYP2C (CYP2C8 and CYP2C18) mRNA expression in all of the 14 bronchial mucosa specimens. CYP2A6 and CYP2B6 mRNAs were found in 85% of the samples, whereas 50 and 90% of the tissues displayed CYP2E1 and CYP3A5 expression, respectively. However, CYP1A2, CYP2D6 and CYP3A4 mRNAs were not detected in all samples analysed. Normal human bronchial epithelial cells (NHBE cells) cultured in serum-free conditions showed reduced P450 expression in comparison with the bronchial mucosal samples. Similar to the bronchial mucosa, the peripheral lung tissues expressed CYP1A1, CYP2A6, CYP2B6, CYP2C (CYP2C8 and CYP2C18), CYP2E1 and CYP3A5 mRNAs, but did not show detectable levels of CYP2D6. Additional P450s, such as CYP1A2 and CYP3A4, were detected. The expression of CYP1A1, CYP1A2, CYP2B6, CYP2E1 and CYP3A4/5 in peripheral lung tissues was confirmed at the protein level, whereas CYP2A6 protein was undetectable. The use of specific primers for the detection of the phase II isoenzymes belonging to the glutathione S-transferase mu (GST mu) and N-acetyl transferase (NAT) families showed that GSTM1 was expressed in 40% of the bronchial mucosa and 25% of the peripheral lung tissues, whereas GSTM3 and NAT1 mRNAs were found in all bronchial and lung samples. Finally, NAT2 expression was detected in all peripheral lung tissues, but was not detected in the bronchus. In conclusion, these results describing the diversity of the xenobiotic-metabolising enzymes expressed in the bronchus and lung tissues indicate that the human respiratory system could significantly and specifically contribute to the activation and metabolism of several environmental procarcinogens.
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PMID:Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues. 979 7

Maternal smoking increases the risk of spontaneous abortion. Polymorphic N-acetyltransferase (NAT2) and glutathione S-transferase (GSTM1) affect metabolism of some mutagens found in tobacco smoke. Genotypes and smoking were studied in women with at least two spontaneous abortions (N = 32) and those with at least two livebirths (N = 179). Smoking slightly increased risk (odds ratio = 1.3; 95% confidence interval = 0.6-2.9), but NAT2 and GSTM1 did not. NAT2 or GSTM1 polymorphisms did not appreciably modify smoking-related risk.
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PMID:Risk of recurrent spontaneous abortion, cigarette smoking, and genetic polymorphisms in NAT2 and GSTM1. 979 79


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