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 effects of 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-TCDD) on drug-metabolizing enzymes were studied in male and female rats. 1,2,3,4-TCDD (25, 50, 100 and 200 mumol/kg) was administered by i.p. injection once. Among the cytochrome P-450 (P450)-mediated monooxygenase activities tested, 7-ethoxyresorufin O-deethylase (EROD) activities in both male and female rats, which are associated with CYP1A1, were remarkably induced by all doses of 1,2,3,4-TCDD. The relative induction to each control activity were from 3.0- to 24.5-fold and from 2.2- to 16.5-fold, respectively. Also, 1,2,3,4-TCDD increased other CYP1A-mediated monooxygenase activities such as 7-ethoxycoumarin O-deethylase (ECOD) and 7-methoxyresorufin O-demethylase (MROD) in male and female rats dose-dependently (1.4- to 4.3-fold). Western immunoblotting showed that the levels of CYP1A1 and CYP1A2 proteins in liver microsomes were increased by 1,2,3,4-TCDD. Although the activities of other P450-mediated monooxygenases, namely 7-pentoxyresorufin O-depentylase (PROD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND) and nitrosodimethylamine N-demethylase (NDAND) in both male and female rats were induced at high doses (> or = 50 mumol/kg) of 1,2,3,4-TCDD, the relative level was low compared with those of the CYP1A-mediated monooxygenase such as EROD, ECOD or MROD. In addition to P450-mediated monooxygenase, there was significant induction in the activities of the Phase II drug-metabolizing enzymes, UDP-glucuronyltransferase (UGT) activities towards 4-nitrophenol (4-NP) and 7-hydroxycoumarin (7-HC) and glutathione S-transferase (GST) towards 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB) and DT-diaphorase. These results indicate that 1,2,3,4-TCDD induces both Phase I (CYP1A-mediated monooxygenase) and Phase II drug-metabolizing enzymes (UGT, GST, DT-diaphorase) in the male and female rat liver, and that the alterations of drug-metabolizing enzyme are characteristic of PCDD toxicity.
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PMID:The effect of 1,2,3,4-tetrachlorodibenzo-p-dioxin on drug-metabolizing enzymes in the rat liver. 786 51

Wild-type MCF-7 human breast cancer cells were cultured for 3 months in 1 microM benzo[a]pyrene (BaP), and resistant clones were screened for inducibility of CYP1A1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One of the BaP-resistant (BaPR) clones exhibited unique genotypic expression which distinguished it from both wild-type and drug-resistant (AdrR) variant MCF-7 cells. Glutathione levels, glutathione S-transferase activities, estrogen receptor levels, estrogen responsiveness, and expression of the multidrug-resistant MDR1 and MRP mRNA levels were similar in the wild-type and BaPR cells, whereas these parameters were reported to be altered in AdrR cells. In contrast, TCDD induced CYP1A1 gene expression and inhibited selected estrogen-induced responses in wild-type but not BaPR MCF-7 cells. Treatment of wild-type and BaPR cells with [3H]TCDD resulted in formation of the radiolabeled aryl hydrocarbon (Ah) 6 S nuclear receptor complex in both cell lines. The loss of Ah responsiveness in the BaPR variant cells correlated with the failure of the nuclear or transformed cytosolic Ah receptor complex to bind genomic dioxin-responsive elements as determined in gel retardation assays.
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PMID:Benzo[a]pyrene-resistant MCF-7 human breast cancer cells. A unique aryl hydrocarbon-nonresponsive clone. 790 15

Genetically based differences in metabolism, related to MspI restriction site and Ile-Val polymorphisms of the cytochrome P450 (CYP) 1A1 gene and the null genotype of glutathione transferase class mu (GSTM1), have been reported to be associated with lung cancer susceptibility. The present study was set up to establish the frequencies of the polymorphic genotypes of CYP1A1 and GSTM1 in Sweden, to evaluate a possible increased incidence of the genotypes associated with higher lung cancer risks among Swedish lung cancer patients and to try to make a combined risk estimate for carriers of multiple risk alleles. In a healthy control group, all under 66 years of age, 53% (174/329) of the subjects were of the GSTM1(-) genotype, while in a hospital control group 49% (39/79) carried the GSTM1(-) genotype. In the investigated lung cancer patients this genotype was found in 56% (165/296) and among those patients diagnosed before 66 years of age the deficient genotype was found in 60% (78/131). The highest proportion of the GSTM1(-) genotype was found in patients diagnosed with adenocarcinoma (63%, 29/46) and small cell carcinoma (72%, 21/29) before 66 years of age and among female squamous cell carcinoma patients (79%, 15/19). The allelic variants in CYP1A1 were equally distributed in lung cancer patients and controls. The m1/m2 and m2/m2 genotypes of the MspI site and the Ile/Val genotype were, however, slightly over-represented in squamous cell carcinoma patients. Among patients with squamous cell carcinoma diagnosed before 66 years of age the m1/m2 genotype was found in 28% (10/36), whereas the same genotype was observed in 16% (52/329) of healthy control subjects. A combined risk of squamous cell carcinoma was indicated for patients, diagnosed before 66 years of age, carrying both GSTM1(-) and m2 alleles (OR = 3.0, 95% CI = 1.2-7.2).
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PMID:Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. 792 70

The effects of 1,2,4-trichlorodibenzo-p-dioxin (1,2,4-TrCDD) on drug-metabolizing-enzymes have been studied in male Wistar rats. 1,2,4-TrCDD (0.1 mmol/kg per day) was administered by i.p. injection for 3 days. Among the cytochrome P-450 (P450)-mediated monooxygenase activities tested, 7-ethoxyresorufin O-deethylase, which is associated with CYP1A1, was remarkably induced by 1,2,4-TrCDD (0.1 mmol/kg). The relative induction to control activity was 32.9-fold. Also, 1,2,4-TrCDD increased other CYP1A-mediated monooxygenase activities such as 7-ethoxycoumarin O-deethylase, 4-nitroanisole O-demethylase, 7-methoxyresorufin O-demethylase and caffeine N-demethylase from 5.7- to 1.9-fold. Western immunoblotting showed that the levels of CYP1A1 and CYP1A2 proteins in liver microsomes were increased by 1,2,4-TrCDD. On the other hand, 7-pentoxyresorufin O-depentylase activity was induced 2.6-fold whereas aniline 4-hydroxylase, nitrosodimethylamine N-demethylase and erythromycin N-demethylase activities were increased slightly (1.3-, 1.6- and 1.3-fold, respectively) by 1,2,4-TrCDD. However, aminopyrine N-demethylase was not significantly induced by 1,2,4-TrCDD. Of the Phase II drug-metabolizing enzymes, DT-diaphorase and glutathione S-transferase (GST) activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and those of UDP-glucuronyltransferase (UGT) towards 4-nitrophenol and 7-hydroxycoumarin were increased from 2.7 to 1.4-fold by 1,2,4-TrCDD. These results indicate that 1,2,4-TrCDD induces both Phase I and Phase II drug-metabolizing enzymes in the rat liver.
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PMID:Effect of 1,2,4-trichlorodibenzo-p-dioxin on drug-metabolizing enzymes in the rat liver. 795 69

Aromatic DNA adducts in total white blood cells, cytochrome P450 (CYP) class 1A1 and glutathione transferase (GST1) class mu genotypes and micronuclei in T- and B-lymphocytes were studied in 69 full-time chimney sweeps and 35 controls, all male subjects. The sweeps had a higher (22%) but statistically non-significant increase in the level of DNA adducts as compared to the controls when all individuals independent of genotype were compared. The non-inducible CYP1A1 genotype, m1/m1, lacking a MspI restriction site at the 3' end of the gene, was associated with significantly higher adduct levels in the sweeps. Among the 26 sweeps with the combined genotype m1/m1 and GST1(-), a statistically significant 60% increase in median adduct levels was observed as compared with those 14 control subjects with the corresponding genotype. Smoking also showed a significant effect on the level of adducts. The effect on DNA adducts by sweeping, smoking and genotype appeared to be additive and independent of each other. DNA adducts in sweeps were moderately but statistically significantly correlated with micronuclei in both T- and B-lymphocytes. The correlation between adduct levels and micronuclei was most marked in T-lymphocytes of individuals lacking the GST1 gene.
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PMID:Aromatic DNA adducts, micronuclei and genetic polymorphism for CYP1A1 and GST1 in chimney sweeps. 803 10

This data in the aggregate suggests that the 3 best studied genetic susceptibility factors (CYP2D6 extensive metabolizers, GST mu null phenotype, and CYP1A1 "mutant" alleles in Asians only) constitute greater risk factors for the more smoking related histologies of lung cancer, but not for adenocarcinoma. The epidemiologic evidence for a these genetic susceptibility factors in tobacco-related cancer is suggestive but not determinant. A consensus estimate of relative risk for extensive metabolizers of debrisoquine is around 2. Variability in study results depend on a number of factors which include: assay misclassification, non-correspondence of phenotype/genotype in certain subjects, disease heterogeneity, exposure variation, ethnic and racial variation. Future studies should emphasize: a high quality approach to data gathering, careful attention to epidemiologic design, and the use of intermediate markers where feasible. Investigators should consider the use of multiple genetic markers since PCR approaches can make this an efficient approach. A meta-analysis may serve to illuminate points of heterogeneity between studies. New discoveries should provide opportunities to explore for analogous associations in other malignancies. It may be speculated that the "specificity" of the association observed for each of the genetic factors tends to support the general causal nature of the hypothesis. The fact that each shares the histologic preference at least suggests that a common mechanism may be operative. The observation that the tobacco-cancer association, though clearly present, is weaker for adenocarcinoma than for the other lung cancer histologies, suggests that the underlying mechanism involves some interaction of the genetic trait with exposure to tobacco smoking, and suggests further attention to this factor to elucidate differences in risk estimates for genetic susceptibility factors among different studies.
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PMID:Molecular epidemiology: a new perspective for the study of toxic exposures in man. A consideration of the influence of genetic susceptibility factors on risk in different lung cancer histologies. 803 47

A close correlation between cigarette smoking associated lung cancer incidence and an Msp I restriction fragment length polymorphism (RFLP) of the human P-450 1A1 (CYP1A1) gene was found in a Japanese population in terms of genotype frequency and cigarette dose. A Val/Ile codon difference in the primary structure of the CYP1A1 protein (Val-, Ile-type) was in linkage disequilibrium with the Msp I RFLP. A synergistic increase in susceptibility to lung cancer was found when combining genotyping of CYP1A1 and the Mu-class of glutathione S-transferase (GST1). Interindividual variability in the genetic make-up of carcinogen metabolizing enzymes may thus be a key host factor to explain the differences in susceptibility to chemical carcinogenesis among individuals.
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PMID:The CYP1A1 gene and cancer susceptibility. 810 89

1. The expression of P450 isoenzymes in foetal and neonatal hepatic microsomes was determined by measuring the metabolism of marker substrates and by studying the expression of P450 isoenzymes at the protein and mRNA level. 2. Monooxygenase activities were not measurable at day 10 of gestation, but shortly before birth (day 20 of gestation) and thereafter a surge in monooxygenase activities was observed using ethoxyresorufin, aniline, nitroanisole, aminopyrine, dimethylnitrosamine and aldrin as substrates. 3. In contrast, as early as day 10 of gestation, post oxidative drug metabolism was measurable, when assessed for reactions catalysed by UDP-glucuronyltransferase, glutathione S-transferase and epoxide hydrolase. 4. Microsomal proteins isolated from foetal/perinatal rats did not crossreact with antibodies raised to CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1, CYP3A1 and CYP4A1 at a protein loading of 3 micrograms total protein/well. 5. With the exception of CYP2E1 mRNA and CYP4A1 mRNA there was little evidence to suggest the expression of CYP1A1, CYP1A2 and CYP2A1 mRNA. 6. The mRNA of CYP2B1, CYP2C7 and CYP3A1 was not detectable in foetal/perinatal rat liver extracts at a loading rate of 10 micrograms total RNA. 7. Microsomal proteins isolated from neonatal rats crossreacted with antibodies raised to CYP2C6, CYP2E1, CYP3A1 and CYP4A1, albeit at varying intensities. 8. Concomitantly, CYP2A1, CYP2E1 and CYP4A1 mRNA transcripts were detectable in Northern blot hybridization experiments using neonatal rat liver RNA extracts.
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PMID:Expression of P450 isoenzymes during rat liver organogenesis. 828 35

We characterized the inducing effects of two musk analogues, musk xylene and musk ambrette, on phase I and phase II drug-metabolizing enzymes in rat liver and compared their effects with 3-methylcholanthrene, isosafrole and 2(3)-tertbutylhydroxyanisole (BHA) at 0.1 mmol/kg dose level. Musk xylene and isosafrole increased more efficiently the metabolic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) to mutagen than that of benzo(a)pyrene. Musk ambrette increased both the activation of Glu-P-1 and benzo(a)pyrene to the same extent. Western blot analyses revealed that musk xylene, musk ambrette, isosafrole and BHA induced more strongly cytochrome P450 1A2 (CYP1A2) in microsomes than CYP1A1. 3-Methylcholanthrene induced CYP1A1 in preference to CYP1A2. On the other hand, all drugs except for 3-methylcholanthrene did not show remarkable increases in phase II enzyme activities, such as DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase, at 0.1 mmol/kg dose level. These results show that musk xylene, musk ambrette, isosafrole and BHA at the dose level used in this study possess the potency to induce CYP1A2 without remarkable induction of CYP1A1 and phase II enzyme activities as observed for 3-methylcholanthrene, although they have been considered to induce both phase I and phase II drug-metabolizing enzymes at higher doses.
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PMID:Induction of cytochrome P450 1A2 by musk analogues and other inducing agents in rat liver. 829 89

An association of lung cancer susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene was reported in our previous study. This polymorphism has been subsequently found to be closely linked to another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of P4501A1. We report here that genetic risk for squamous cell carcinoma of the lung was associated with these two polymorphisms of the CYP1A1 gene in terms of genotype frequencies and cigarette-smoking dose and that a more increased risk was observed for the individuals with "susceptible" genotypes of CYP1A1 combined with a deficient genotype of a mu-class glutathione S-transferase (GST1), which detoxifies the electrophilic metabolites of aromatic hydrocarbon procarcinogens activated by P4501A1. We first compared the total amounts of cigarettes consumed during a lifetime among 85 patients with squamous cell carcinoma of the lung, whose CYP1A1 and GST1 genes were identified. The patients with a susceptible homozygote of each of the MspI and Ile-Val polymorphisms contracted the carcinoma after smoking fewer cigarettes than those with other genotypes. When the GST1 polymorphism was taken into account, the cumulative cigarette amounts in combined genotyping of the two genes showed distinct differences, resulting in the lowest cigarette dose observed for the patients with a susceptible MspI or Ile-Val genotype of CYP1A1 combined with a deficient GST1 homozygote. Next, a case-control study revealed that the individuals with the susceptible MspI or Ile-Val genotype combined with deficient GST1 were at remarkably high risk with an odds ratio of 16.00 or 41.00, respectively (95% confidence interval, 3.76-68.02 or 8.68-193.61, respectively), at a low dose level of cigarette smoking.
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PMID:Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. 831 7


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