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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the health effects of gasoline exposure on liver function test indices of filling station workers the present study was done. This case-control study was conducted in Shiraz on 56 male gasoline workers and 56 age- and sex-matched control subjects with no occupational exposure to gasoline. To elucidate the role of hepatic detoxifying enzymes, the genotypes of glutathione-S-transferases (GST) M1 and T1 were determined. Data analysis was done by multiple linear regression analysis and non-parametric Kruskal-Wallis test. The present study showed that all measurements were in normal range, although sub-clinical changes were detected in some indices. In liver function tests, exposure was associated with lower serum albumin (t=-3.88, P<0.001) and total proteins (t=-3.016, P=0.003) but higher alanine aminotransferase (t=2.856, P=0.005) and aspartate aminotransferase (t=2.11, P=0.038) levels in workers comparing to controls. Other investigators reported that GSTs involved in detoxification of several toxins including some of the compounds present in gasoline. Therefore, the possible influence of GSTT1 and GSTM1 genetic polymorphisms on alteration of liver function tests indices was investigated. The present findings showed that the genotype combinations of GSTM1 and GSTT1 did not alter the effects of exposure to gasoline in workers except for serum albumin. Serum albumin significantly decreased in workers with both active GST enzymes who had more than 5 years of employments (P=0.01). It is suggested that GSTM1 and GSTT1 are not involved in detoxification of toxicants present in gasoline which are hazardous to liver. Overall, due to detection of sub-clinical changes in hepatic test in gasoline station workers, exposure limitation and administrating safety device are recommended.
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PMID:Alterations of liver function test indices of filling station workers with respect of genetic polymorphisms of GSTM1 and GSTT1. 1589 22

Dimethylformaide (DMF) is a major solvent predominately used in synthetic leather and resin production. Many human and animal studies have linked the cause of hepatoxicity to DMF. Previously, the authors demonstrated the significant dose-response relationship between abnormal liver function tests and DMF exposure and the interaction with hepatitis B virus (HBV) infection in Taiwanese workers. Because the toxic effect of various chemicals can be modified by metabolic traits, the study also investigated the influence of the glutathione S-transferases (GSTM1 and GSTT1) on the toxic effect of DMF. The average DMF exposure concentration was 23.87 ppm (range 5.2-86.6 ppm) in the high-exposure (>/=5 ppm) group and 2.41 ppm (range 0.9-4.3 ppm) in the low-exposure (<5 ppm) group. There were 13 of 44 (29.6%) abnormal liver function tests (elevations of either glutamate oxaloacetate transaminase (GOT) or glutamate pyruvate transaminase (GPT)) among the high DMF exposure workers, two of 22 (9.1%) abnormal liver function tests among the low DMF exposure workers. Chronic liver disease as determined by ultrasonography was present in seven of 44 (15.9%) high DMF exposure workers, and 0 of 22 (0%) low DMF exposure workers. There were 11 of 34 (32.4%) abnormal liver function tests among the GSTT1 null genotype workers, and four of 32 (12.5%) abnormal liver function tests among the GSTT1-positive genotype workers. Compared with the low DMF exposure workers, the adjusted odds ratio and 95% confidence intervals for abnormal liver function tests was 6.78 (0.94-48.7) for the high DMF exposure workers. Compared with the GSTT1-positive genotype workers, the adjusted odds ratio and 95% confidence intervals for abnormal liver function tests was 4.41 (1.15-16.9) for the GSTT1 null genotype workers. Compared with the low DMF group with GSTT1-positive genotype workers, the odds ratio (adjusted for HBV status) of abnormal liver function test was 12.38, 95% CI=(1.04-146.9) for the high DMF group with GSTT1 null genotype workers. This study indicates that abnormal liver function and chronic liver disease are associated with DMF exposure, and there are more than multiplicative interaction effects on abnormal liver function tests between the DMF exposure and the GSTT1 genotype.
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PMID:Abnormal liver function associated with occupational exposure to dimethylformamide and glutathione S-transferase polymorphisms. 1630 70

The double null mutation of glutathione transferase, GSTM1 and GSTT1, is reported to influence troglitazone-associated abnormal increases of alanine aminotransferase and aspartate aminotransferase. However, no nonclinical data with a bearing on the clinical outcomes and underlying mechanisms have hitherto been reported. To investigate whether deficiency in GSTM1 and/or GSTT1 is related to troglitazone hepatotoxicity in vitro, the covalent binding level (CBL) (an index of reactive metabolite formation) and cytotoxicity of troglitazone and rosiglitazone, another thiazolidinedione but with low hepatotoxicity, were examined using human liver samples phenotyped for cytochrome P450s and genotyped for GSTM1 and GSTT1. Despite addition of GSH, CBLs of troglitazone and rosiglitazone in human liver microsomes were correlated with CYP3A (or CYP2C8) and CYP2C8 activities, respectively. With addition of recombinant GSTM1, the microsomal CBLs of troglitazone and rosiglitazone decreased. However, the CBLs of troglitazone in GSTM1/GSTT1 wild-type hepatocytes were unexpectedly higher than those in null hepatocytes. Although this discrepancy has not been fully explained, the GSTM1 and GSTT1 null mutations increased the cytotoxicity of troglitazone, independent of CYP3A or CYP2C8 activities. Furthermore, a GSH adduct of troglitazone, M2, limited to GSTM1 wild-type hepatocytes was detected. Of clear interest, GSTM1 and/or GSTT1 null mutation-dependent cytotoxicity and higher exposure to the reactive metabolite trapped as M2 as for troglitazone were not observed for rosiglitazone. This result might at least partly explain the findings related to clinical hepatotoxicity, suggesting that measurement of GSH adducts or cytotoxicity using GSTM1- and GSTT1-genotyped hepatocytes might offer an important in vitro system to assist in better prediction of idiosyncratic hepatotoxicity.
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PMID:In vitro investigation of the glutathione transferase M1 and T1 null genotypes as risk factors for troglitazone-induced liver injury. 2151 44

Null mutation of glutathione transferase (GST) M1 and GSTT1 was reported to correlate statistically with an abnormal increase in the plasma levels of alanine aminotransferase or aspartate aminotransferase caused by troglitazone in diabetic patients (Clin Pharmacol Ther, 73:435-455, 2003). This clinical evidence leads to the hypothesis that GSH conjugation catalyzed by GSTT1 and GSTM1 has a role in the elimination of reactive metabolites of troglitazone. However, the contribution of GST isoforms expressed in human liver to the detoxification of reactive metabolites of troglitazone has not yet been clarified. We investigated the involvement of human GST isoforms in the GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes. Five reported GSH conjugates of reactive metabolites were produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner. Addition of human recombinant GSTA1, GSTA2, GSTM1, or GSTP1 protein to the incubation mixture further increased the GSH conjugates. However, the addition of GSTT1 did not show any catalytic effect. It is of interest that one of the reactive metabolites with a quinone structure was predominantly conjugated with GSH by GSTM1. Thus, we demonstrated that the GST isoforms contributed differently to the GSH conjugation of individual reactive metabolites of troglitazone, and GSTM1 is the most important GST isoform in the GSH conjugation of a specific reactive metabolite produced from the cytotoxic, quinone-form metabolite of troglitazone.
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PMID:Involvement of different human glutathione transferase isoforms in the glutathione conjugation of reactive metabolites of troglitazone. 2191 35

Most chemotherapy treatments induce DNA damage in the exposed patients. Using the comet assay and peripheral blood mononuclear cells (PBMC), we have quantified this induced DNA damage and studied its relationship with GSTM1 and GSTT1 polymorphisms, and clinical parameters. For this purpose, 29 Caucasian women, breast cancer patients under CMF or CEF adjuvant chemotherapy were included in the study. The clinical parameters considered were (i) therapies side effects, like haematological and biochemical toxicities, (ii) prognostic and predictive factors, like hormonal receptor expression, tumour differentiation degree, sickness stage, and nodal status, and (iii) the effectiveness of the chemotherapy measured as five years relapse probability. The results were also related to the confounding factor age. Comet assay results indicate that 13 patients were characterised by absence of induced DNA strand breaks, and 16 patients presented induced DNA strand breaks along the treatment. Relationships between comet variables and clinical parameters, found with principal component analysis, correlations, one-way ANOVA and multivariate logistic regression analyses revealed that: (1) baseline levels of DNA damage are related to GSTM1 genotype and to hormonal receptor expression; (2) GSTM1 genotype also influences comet results after chemotherapy, as it does the AST level; (3) the tail moment values of the cycle 6.1 and the sickness stage might predict cancer relapse at five years: for the Stage, OR = 13.8 (IIB versus I+IIA), 95% CI 0.80-238.97, and for 6.1 cycle TM, OR = 1.3, 95%, CI 0.97-1.79, with a potential model (10* Stage (I-IIA = 0, IIB = 1) + 6.1 cycle), that has a good predictive capacity, with an area under ROC curve of 0.872 (CI 0.62-1.00). To our knowledge, this is the first time such a predictive value is found for the comet assay. Nevertheless, before the comet assay could be used as a tool for oncologists, this relationship should be confirmed in more patients, and problems of standardisation and data interpretation should be solved.
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PMID:Long-term biomonitoring of breast cancer patients under adjuvant chemotherapy: the comet assay as a possible predictive factor. 2298 25

The relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver biomarkers was investigated in individuals under anti-tuberculosis drug therapy. Tuberculosis outpatients (18-70 y) with (n=59) and without (n=40) mild increase of liver enzymes (MILE) at two-month treatment were selected. Blood samples were obtained for DNA extraction and evaluation of serum markers of liver function. NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms were detected by DNA sequencing, PCR-RFLP, and PCR multiplex. Frequency of NAT2*5/*5 genotype was higher in MILE than in non-MILE group (p=0.04). Patients carrying NAT2*5/*5 genotype had increased susceptibility to MILE (OR: 9.00, 95CI: 1.46-55.48, p=0.018). CYP2E1*5B allele (*1A/*5B plus *5B/*5B genotypes) carriers had a trend for reduced risk for MILE (OR: 0.34, 95CI: 0.11-1.03, p=0.056) that was confirmed by lower levels of liver markers than CYP2E1*1A/*1A carriers after treatment (p<0.05). Moreover, increased post-treatment ALT, AST and total bilirubin were associated with GSTM1*1/GSTT1*1 genotypes (p<0.05). Patients taking CYP2E1 inhibitors had increased susceptibility to MILE (OR: 7.39, 95CI: 1.93-28.29, p=0.003), which was independent of the studied polymorphisms. These results are suggestive that NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms and concomitant use of CYP2E1 inhibitors contribute to the susceptibility to mild alterations in liver enzymes in patients under anti-tuberculosis drug therapy.
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PMID:Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy. 2309 18

Toxicity refers to the potential of a substance such as a pesticide to cause damage to the structure or functions of an exposed organism. Pesticides can lead to harmful biological effects in exposed animals and their offspring over the medium and long term. They can affect the immunological, nervous, endocrine, and reproductive systems. DNA damage has also been linked to exposure to pesticides, and this damage can cause abortions, degenerative diseases, and cancer. The aim of this work was to establish whether women who are indirectly exposed to pesticides exhibit a compromised health status, including genotoxic effect. Women exposed indirectly to pesticides in Chimchanga and Colaisaca in the south of Ecuador underwent hematological and biochemical tests and micronucleus assay in buccal cells. The subjects were also genotyped for GSTM1, GSTT1, GSTP1, and PON1 polymorphisms, which can modify an individual's capacity to metabolize pesticides and relation with damage of DNA. The study revealed hepatic toxicity in Colaisaca women (AST and ALT) and an increase in the rate of micronucleus (MN) in Colaisaca individuals. In addition, genetic polymorphisms in PON1 and GSTP1 showed effects of modulating the frequency of karyolytic cells, karyorrhectic cells, and condensed chromatin cells.
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PMID:Biochemical and genotoxic effects in women exposed to pesticides in Southern Ecuador. 3124 55

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