Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indole-3-carbinol (I3C) was examined for its ability to inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in male Fischer rats when administered either before or after the carcinogen. After 13 weeks, animals pretreated with I3C (0.5% in the diet) for 2 weeks prior to administration of AFB1 and with continuing treatment during exposure to the carcinogen were protected from development of preneoplastic lesions, as determined by the classical markers gamma-glutamyltranspeptidase (GGT) and glutathione S-transferase (GST) P. In animals receiving AFB1 for 6 weeks before treatment with I3C, there was no obvious protective effect at 13 weeks compared with animals receiving only AFB1. Using cytokeratin 18 expression as a marker, animals fed AFB1 alone had a small number of positive foci at 13 weeks. However, no cytokeratin-positive foci were visible in the majority of livers from either group receiving I3C in combination with AFB1 and after 43 weeks all animals in these groups were protected from liver tumour formation. These results suggest that expression of cytokeratin 18, a later phenotypic change in foci than induction of GST-P and GGT, correlates more closely with tumour outcome in this model. I3C appeared to retard progression of AFB1-induced carcinogenesis at both the initiation and promotion stages. Continuous treatment with I3C for 13 weeks caused significant induction of CYP1A1, 1A2, 3A and 2B1/2, GST Yc2, aflatoxin B1 aldehyde reductase and quinone reductase. Such alteration of the drug metabolizing capacity of the liver by I3C contributes to blocking of initiation, while the observed inhibition of ornithine decarboxylase, a rate limiting enzyme in polyamine biosynthesis, and of tyrosine kinase activity may contribute to the suppressive effect of I3C.
 ...
PMID:Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver--predicting the outcome using early biomarkers. 980 66

Glutathione S-transferase placental form (GST-P), one of the glutathione S-transferases family of detoxification enzymes, is a very useful marker of rat liver pre-neoplastic lesions. We here investigated the gene expression profile in GST-P positive foci as compared with surrounding GST-P negative areas in the same liver of rats treated with diethylnitrosamine and then 2-acetylaminofluorene combined with partial hepatectomy. GST-P positive foci were harvested by laser microdissection and total RNAs were extracted to allow gene expression profiles to be assessed by cDNA microarray assays. Transaldolase, rat aflatoxin B1 aldehyde reductase and gamma-glutamylcysteine synthetase were found as up-regulated genes and regucalcin as a down-regulated gene, in line with findings for hepatocellular carcinomas. The results indicate that the approach adopted is useful for understanding mechanisms of hepatocarcinogenesis and identification of new markers for rat liver pre-neoplastic foci.
 ...
PMID:Specific differences in gene expression profile revealed by cDNA microarray analysis of glutathione S-transferase placental form (GST-P) immunohistochemically positive rat liver foci and surrounding tissue. 1465 48

Sulforaphane (SUL) is one member of the isothiocyanate class of cancer chemopreventive compounds that has been shown to be effective in blocking initiation and progression of carcinogenesis. Previously, many studies have shown that SUL can potently induce phase II detoxifying enzymes, which contributes to its chemopreventive functions. In this study, we used 4967 oligonucleotides microarray to assess the genes that are modulated by SUL in in vivo rat livers, as well as time course of expression of these genes. The pharmacokinetics of SUL was assessed after oral dose of 50 micromol of SUL. The plasma concentration occurred at 1 h and peaked around 20 microM at 4 h after dosing and declined with a half-life of about 2.2 h. Analysis of the gene expression data found various clusters of genes that are important in cellular defense mechanisms and cell cycle regulation. The most robust cluster of genes is the metallothionein-like genes (MT-1/2 and MT-1a), which are increased up to 10-fold by 2 to 4 h after SUL dosing. The second cluster of genes is the glutathione S-transferase-A3-like genes, which include aflatoxin B1 aldehyde reductase and aldehyde oxidase. These genes are increased slightly by 4 h and peaked at 12 h. Real-time polymerase chain reaction was performed to authenticate the mRNA expression of some of these genes. In summary, this in vivo study of SUL provides the first clue as to the plasma concentrations of SUL, in vivo mitogen-activated protein kinase activations in rat livers, as well as what other genes are modulated in addition to phase II detoxifying genes. The results from this study may yield better insights for its chemopreventive functions.
 ...
PMID:In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat. 1498 20

Today, toxicoproteomics still relies mainly on 2-DE followed by MS for detection and identification of proteins, which might characterize a certain state of disease, indicate toxicity or even predict carcinogenicity. We utilized the classical 2-DE/MS approach for the evaluation of early protein biomarkers which are predictive for chemically induced hepatocarcinogenesis in rats. We were able to identify statistically significantly deregulated proteins in N-nitrosomorpholine exposed rat liver tissue. Based on literature data, biological relevance in the early molecular process of hepatocarcinogenicity could be suggested for most of these potential biomarkers. However, in order to ensure reliable results and to create the prerequisites necessary for integration in routine toxicology studies in the future, these protein expression patterns need to be prevalidated using independent technology platforms. In the current study, we evaluated the usefulness of iTRAQ reagent technology (Applied Biosystems, Framingham, USA), a recently introduced MS-based protein quantitation method, for verification of the 2-DE/MS biomarkers. In summary, the regulation of 26 2-DE/MS derived protein biomarkers could be verified. Proteins like HSP 90-beta, annexin A5, ketohexokinase, N-hydroxyarylamine sulfotransferase, ornithine aminotransferase, and adenosine kinase showed highly comparable fold changes using both proteomic quantitation strategies. In addition, iTRAQ analysis delivered further potential biomarkers with biological relevance to the processes of hepatocarcinogenicity: e.g. placental form of glutathione S-transferase (GST-P), carbonic anhydrase, and aflatoxin B1 aldehyde reductase. Our results show both the usefulness of iTRAQ reagent technology for biomarker prevalidation as well as for identification of further potential marker proteins, which are indicative for liver hepatocarcinogenicity.
 ...
PMID:Prevalidation of potential protein biomarkers in toxicology using iTRAQ reagent technology. 1744 45

The glutathione S-transferase (GST) and aldo-keto reductase (AKR) families of proteins are major groups of detoxifying enzymes that are known to be regulated by the NF-E2 related factor 2 (Nrf2) transcription factor via the antioxidant response element that is present in the promoter regions of GST and AKR genes. Expression of Nrf2, GST and AKR proteins was analyzed in the African clawed frog, Xenopus laevis, focusing on their responses to dehydration stress. Dehydration/rehydration cycles can generate oxidative stress and this could be ameliorated by enhancing antioxidant defenses. Dehydration to 28% of total body water lost triggered organ-specific changes in nrf2 mRNA expression (a 2-fold increase in liver), total Nrf2 protein (2-4-fold elevation in lung, heart, skin and liver), and a 4.3-fold increase in the content of Nrf2 in the nucleus in muscle. Protein levels of six GST and three AKR family members were assessed and showed organ-specific patterns of expression during dehydration. In particular, GSTP1 was strongly induced in liver, heart and skin, levels rising by 9-, 2.6- and 1.7-fold, respectively, whereas GSTM1 and M3 rose in skeletal muscle, kidney and skin. Selective expression of GSTK1, A3 and T1 also occurred. Dehydration also stimulated organ-specific increases in the levels of AKR family members (AKR1B4, AKR1A3, AFAR1) by 1.5-2-fold. The results show that metabolic responses to dehydration include activation of the Nrf2 transcription factor and selective up-regulation of genes under Nrf2 control.
 ...
PMID:Activation of antioxidant defense during dehydration stress in the African clawed frog. 1937