Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The T-cell cloning assay which combines mitogen- and growth factor-dependent expansion of lymphocyte clones with thioguanine selection of hypoxanthine-guanine phosphoribosyl transferase (hprt)-negative cells has been extensively used for studying human somatic gene mutation in vivo. However, large interindividual variations in the hprt mutant frequency (MF), much of which is not explained by donor attributes such as age and smoking habit, and interlaboratory variations in the experimental methodology, including cloning efficiency (CE), call for further developments of the cloning protocol and additional population studies. Using an improved T-cell cloning method, we have studied in vivo hprt MF of 76 non-smoking healthy males aged 23-77 years. The addition of 5% human serum to the growth medium was found to produce a consistently high CE of 61% in average. The MF, ranging from 1.4 to 22.6 x 10(-6) with a mean of 8.6 x 10(-6), increased significantly (P < 0.0001) with age, by 2% per year. A significant (P = 0.002) inverse relationship between MF and CE was observed. Using a PCR-based technique for GSTM1-genotyping, we also studied the relationship between MF and GSTM1 polymorphism. The 38 (50%) GSTM1-negative individuals showed a 20% higher mean MF than the 38 (50%) GSTM1-positive individuals. The difference was however not significant, neither before (P = 0.1) nor after (P = 0.5) correction for CE and the significantly (P = 0.04) higher mean age in the GSTM1-negative group. This study shows that age contributes more than GSTM1 polymorphism to the large interindividual variation in the hprt MF of non-smokers. The relationship between GSTM1 polymorphism and hprt MF in smokers remains to be investigated.
Environ Mol Mutagen 1995
PMID:Hprt mutant frequency and GSTM1 genotype in non-smoking healthy individuals. 769 12

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.
J Mol Med (Berl) 1995 Nov
PMID:Molecular basis of polymorphic drug metabolism. 875 Nov 38

To investigate mechanisms causing p53 mutations in lung cancer cases, relations between p53 gene mutations and aetiological factors such as smoking history or family history of cancers cases. The contribution of genotypes related to carcinogen metabolism (CYP1A1 and GSTM1) was also analysed. p53 mutations were observed in 13 cases (37.5%). Seven (53.8%) of the 13 patients with p53 mutation compared with five (22.7%) of 22 patients without had a family history of cancer. However, there was no significant relation between p53 mutation or family history of cancer and CYP1A1 or GSTM1 genotypes. In conclusion, p53 mutation might be associated with the inherited characteristics that result in familial aggregation of lung cancer; however, this association was not explained by genotypes of enzymes related to carcinogen metabolisms.
Mol Pathol 1997 Apr
PMID:p53 gene mutations, and CYP1A1 and GSTM1 genotypes in pulmonary squamous cell carcinomas. 923 Nov 61

Significant interindividual variations in health outcome may be caused by the inheritance of variant polymorphic genes, such as CYP2D6 and CYP2E1 for activation, and GSTM1 and GSTT1 for detoxification of chemicals. However, mechanistic studies linking the inheritance of predisposing genes with genotoxic effects towards cancer have yet to be systematically conducted. We have studied 54 lung cancer patients and 50 matched normal controls, who have been cigarette smokers, to elucidate the role of polymorphic genes in cancer. Our data indicates that the inheritance of unfavorable CYP2D6, CYP2E1, and GSTT1 genes in strongly correlated with the smoking-related lung cancer. For heavy cigarette smokers (> 30 pack-years), the smoking habit is the strongest predictor of lung cancer risk irrespective of the inheritance of unfavorable metabolizing genes. For moderate to light smokers (< 30 pack-years), the genetic predisposition plays an important role for the risk (odds ratio = 3.46; 95% Cl = 0.46-40.2). Using a subgroup of the study population, we observed that cigarette smokers having the defective GST genes have significantly more chromosome aberrations as determined by the fluorescence-in-situ-hybridization (FISH) technique than smokers with the normal GST genes (P < 0.001). In conclusion, our study provides data to indicate that individuals who have inherited unfavorable metabolizing genes have increased body burden of toxicants to cause increased genetic damage and to have increased risk for cancer. Studies like ours can be used to understand the basis for interindividual variations in cancer outcome, to identify high risk individuals and to assess health risk.
Environ Mol Mutagen 1997
PMID:Interactions between genetic predisposition and environmental toxicants for development of lung cancer. 932 44

The mu class glutathione S-transferase gene GSTM1 is polymorphic in humans, with approximately half of the Caucasian population being homozygous deleted for this gene. GSTM1 enzyme deficiency has been suggested to predispose people to lung and bladder cancer. Some people in a Saudi Arabian population, however, have been described previously with ultrarapid GSTM1 enzyme activity. Here we have evaluated the molecular genetic basis for this observation. Genomic DNA from two Saudi Arabian subjects exhibiting ultrarapid enzyme activity and from 13 Swedish subjects having null, one, or two GSTM1 genes were subjected to restriction fragment length polymorphism analysis using the restriction enzymes EcoRI, EcoRV, and HindIII and combinations thereof. Hybridization was carried out using a full-length GSTM1 cDNA or the 5' and 3' parts of the cDNA. The restriction mapping data revealed the presence of a GST mu cluster with two GSTM1 genes in tandem situated between the GSTM2 and GSTM5 genes. A quantitative multiplex polymerase chain reaction method, which simultaneously amplified a fragment of the GSTM1 gene and the beta-globin gene, was developed, and the genomic GSTM1 copy number was determined from the GSTM1/beta-globin ratio. This method clearly separated GSTM1 +/- subjects (ratios between 0.4 and 0.7) from GSTM1 +/+ subjects (ratios between 0.8 and 1.2). The two Saudi Arabians with ultrarapid GSTM1 activities had ratios of approximately 1.5, indicating that they carried three GSTM1 genes. These results demonstrate the existence of a novel mu class GST cluster containing a duplicated active GSTM1 gene causing ultrarapid enzyme activity.
Mol Pharmacol 1997 Dec
PMID:Characterization of a human glutathione S-transferase mu cluster containing a duplicated GSTM1 gene that causes ultrarapid enzyme activity. 941 5

The genetic polymorphisms of glutathione S-transferases (GSTs), which are involved in the metabolic inactivation of various toxicants, have been suggested to be an important source of variation in individual response to genotoxic carcinogens. We have previously shown that donor GSTM1 genotype does not influence the induction of sister chromatid exchanges (SCEs) in cultured human lymphocytes by styrene-7,8-oxide (SO), a metabolite of styrene. Here, we expanded the study to GSTT1 polymorphism. SCEs were analyzed from 72-hr whole-blood lymphocyte cultures of five GSTT1 positive (at least one undeleted allele) and five GSTT1 null (gene homozygously deleted) donors, all GSTM1 positive, after a 48-hr treatment with 50 microM and 150 microM SO. SO clearly increased SCEs in cultures of all donors. The mean number of SCEs/cell induced by SO (individual mean SCEs from acetone-treated control cultures subtracted) was 1.7 (50 microM) and 1.4 (150 microM) times greater among the GSTT1 null individuals (4.83 at 50 microM, 18.98 at 150 microM) compared with the GSTT1 positive individuals (2.78 at 50 microM, 13.74 at 150 microM), the differences being statistically significant (P=0.006 and P=0.022, respectively). These findings show that the lack of the GSTT1 gene increases the genotoxic effects of SO in human whole-blood lymphocyte cultures, suggesting that GSTT1 is involved in the detoxification of SO in humans. Although glutathione conjugation is considered a minor metabolic pathway for SO in vivo, the high GSTT1 activity in erythrocytes may be important locally and might affect the level of genotoxic damage observed in peripheral lymphocytes of styrene-exposed reinforced plastics workers. The GSTT1 polymorphism could also influence the urinary excretion of SO-specific mercapturic acids.
Environ Mol Mutagen 1998
PMID:Influence of GSTT1 genotype on sister chromatid exchange induction by styrene-7,8-oxide in cultured human lymphocytes. 965 39

The levels of expressions and catalytic activities of cytochrome P450 (CYP1A1) and glutathione-S-transferase class mu (GSTM1) enzymes in lungs and their metabolic balance may be an important determinant host factor underlying lung cancer. Genetic differences in metabolism, MspI restriction sites, Ile-Val polymorphism of CYP1A1 gene, and the null genotype of GSTM1 have been reported to be associated with susceptibility to lung cancer. The present studies were undertaken to establish frequencies of the polymorphic genotypes of CYP1A1 and GSTM1 in Koreans, and to evaluate linkage disequilibrium of the genotypes associated with higher lung cancer risks among Koreans. GSTM1(-) genotype was found in 52% of control subjects, whereas it was found in 55% of lung cancer patients. The allelic variants in CYP1A1 were distributed differently in lung cancer patients and controls. The heterozygous genotype frequency of the MspI site in lung cancer patients (53%) was higher than in controls (49%). The frequency of Ile/Val genotype of CYP1A1 was low in lung cancer patients, which are mostly squamous cell carcinoma.
Exp Mol Med 1998 Dec 31
PMID:Polymorphism of the CYP1A1 and glutathione-S-transferase gene in Korean lung cancer patients. 989 48

Wide inter-individual variation of expression of compound metabolic enzymes is determined by polymorphism and may predispose the development of diseases provoked by environmental factors. The combined analysis of phase II detoxification system genes: arylamine N-acetyltransferase 2 (NAT2), and glutathione S-transferases (GST) M1 and T1 was carried out in patients with minimal/mild (group I; n = 36) and moderate/severe endometriosis (group II; n = 29) and controls (n = 72) of French origin, using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The results show a significant difference between patients and controls with regard to NAT2 gene polymorphism (P < 0.05). This is mainly due to the high percentage of slow acetylator genotypes (SA) in patients compared with controls (60.0 versus 38.9%; P < 0.02) with a distinct preponderance in subjects with minimal/mild endometriosis (69.4%, P < 0.005) where there is a significantly elevated frequency of slow allele S1 (NAT2*5) (P = 0.05). Significantly increased proportions of GSTM1-deficient genotypes were found in both groups of patients, in comparison with the controls (75.0 and 79.3% versus 45.8%; P < 0. 0001). A preponderance of GSTT1-negative subjects among patients was also detected, but did not appear significant. We suggest the involvement of both NAT2 and GSTM1 detoxification system genes in the pathogenesis of endometriosis and the possible impact of NAT2 gene polymorphism in the development of different forms of this disease.
Mol Hum Reprod 1999 Jul
PMID:Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. 1038 18

A high-throughput genotyping method has been developed to detect gene deletion polymorphisms of glutathione-S-transferase theta and mu (GSTT1 and GSTM1). This method utilizes the 5'-nuclease activity of Taq polymerase in conjunction with fluorogenic TaqMan probes. In contrast to traditional allelic discrimination genotyping to detect single nucleotide polymorphisms, the current assay has been designed to detect gene deletion by utilizing custom-designed TaqMan probes in conjunction with an exogenous internal positive control probe. The TaqMan genotyping results were validated by a commonly used multiplex PCR technique. Screening of 71 unrelated individuals revealed gene deletion (null) genotype of 15.5% and 40.8% for GSTT1 and GSTM1, respectively. This TaqMan genotyping method is rapid, reproducible, and highly sensitive and could be applied toward fully automated large-scale genotyping.
Res Commun Mol Pathol Pharmacol 1999 Jan
PMID:High-throughput genotyping method for glutathione S-transferase T1 and M1 gene deletions using TaqMan probes. 1044 May 66

Glutathione S-transferases (GSTs) are an important part of the protection system against a wide range of potentially harmful chemical compounds. GSTP1 and GSTM1 are mainly involved in detoxification reactions of PAH carcinogenic intermediates produced by cytochrome P450 (CYP). Polymorphism of the GST genes may influence the level of carcinogen-DNA adducts in human tissues and be associated with individual susceptibility to carcinogens. In this study, we examined the effect of common polymorphism in exon 5 (105Ile --> Val) of the GSTP1 gene, alone and in combination with GSTM1-deletion polymorphism, on the level of PAH-DNA adducts measured by (32)P-postlabeling assay in mononuclear white blood cells collected in winter and in summer from a total of 170 healthy volunteers. When GSTP1 genotypes alone were compared, no statistically significant differences in adduct levels were found. However, smokers with GSTM1(null)/GSTP1-AG or -GG combined genotype showed significantly higher adduct levels in summer than carriers of other GSTM1/GSTP1 combinations (5.60 +/- 5.10 vs. 3.45 +/- 4. 28/10(8) nucleotides, P = 0.015). Among smokers carrying GSTP1-AG or -GG genotype, individuals with GSTM1(null) genotype had a significantly higher level of adducts in summer than subjects with GSTM1(+) genotype (5.60 +/- 5.10 vs. 1.82 +/- 1.98/10(8), P = 0.002) and GSTM1(null)/GSTP1-AA genotype carriers (5.60 +/- 5.10 vs. 4.13 +/- 5.84/10(8), P = 0.03). When adduct levels measured either in winter or in the nonsmoker group were considered, no influence of GSTM1/GSTP1 genotypes was found. Our data show that the combined GSTM1 and GSTP1 genetic polymorphisms may modulate PAH-DNA adduct levels in mononuclear WBCs from individuals exposed to specific carcinogenic compounds, e.g., tobacco smoke, in relatively lower-exposure environmental conditions (i.e., in summer).
Environ Mol Mutagen 2000
PMID:Polymorphisms of the GSTP1 and GSTM1 genes and PAH-DNA adducts in human mononuclear white blood cells. 1071 43


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