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)

Metabolism of dichloromethane (DCM) to formaldehyde (HCHO) via a glutathione S-transferase (GST) pathway is thought to be required for its carcinogenic effects in B6C3F1 mice. In humans, this reaction is catalyzed primarily by the protein product of the gene GSTT1, a member of the Theta class of GST, and perhaps to a small extent by the protein product of the gene GSTM1. Humans are polymorphic with respect to both genes. Since HCHO may bind to both DNA and RNA forming DNA-protein crosslinks (DPX) and RNA-formaldehyde adducts (RFA), respectively, these products were determined in isolated hepatocytes from B6C3F1 mice, F344 rats, Syrian golden hamsters, and humans to compare species with respect to the production of HCHO from DCM and its reaction with nucleic acids. Only mouse hepatocytes formed detectable amounts of DPX, the quantities of which corresponded well with quantities of DPX formed in the livers of mice exposed to DCM in vivo [Casanova, M., Conolly, R.B., and Heck, H. d'A. (1996). Fundam. Appl. Toxicol. 31, 103-116]. Hepatocytes from all rodent species and from humans with functional GSTT1 and GSTM1 genes formed RFA. No RFA were detected in human cells lacking these genes. Yields of RFA in hepatocytes of mice were 4-fold higher than in those of rats, 7-fold higher than in those of humans, and 14-fold higher than in those of hamsters. The RFA:DPX ratio in mouse hepatocytes incubated with DCM was approximately 9.0 +/- 1.4, but it was 1.1 +/- 0.3 when HCHO was added directly to the medium, indicating that HCHO generated internally from DCM is not equivalent to that added externally to cells and that it may occupy separate pools. DPX were not detected in human hepatocytes even at concentrations equivalent to an in vivo exposure of 10,000 ppm; however, the possibility that very small amounts of DPX were produced from DCM cannot be excluded, since HCHO was formed in human cells. Maximal amounts of DPXliver that might be formed in humans were predicted from the amounts in mice and the relative amounts of RFA in hepatocytes of both species. With predicted DPXliver as the dosimeter, the unit risk, the upper 95% confidence limit on the cancer risk, and the margin of exposure were calculated at several concentrations using the linearized multistage and benchmark dose methods. Since the actual delivered dose is smaller than that predicted, the results suggest that DCM poses at most a very low risk of liver cancer to humans.
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PMID:Dichloromethane metabolism to formaldehyde and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with and without glutathione S-transferase T1 and M1 genes. 924 90

A recently discovered bacterium, Helicobacter hepaticus, infects the intrahepatic bile canaliculi of mice, causing a severe chronic hepatitis culminating in liver cancer. Thus, it affords an animal model for study of bacteria-associated tumorigenesis including H. pylori-related gastric cancer. Reactive oxygen species are often postulated to contribute to this process. We now report that hepatitis of male mice infected with H. hepaticus show significant increases in the oxidatively damaged DNA deoxynucleoside 8-hydroxydeoxyguanosine, with the degree of damage increasing with progression of the disease. Perfusion of infected livers with nitro blue tetrazolium revealed that superoxide was produced in the cytoplasm of hepatocytes, especially in association with plasmacytic infiltrates near portal triads. Contrary to expectations, Kupffer cells, macrophages, and neutrophils were rarely involved. However, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in many cells, concomitant with severe hepatitis. The CYP2A5 immunohistochemical staining co-localized with formazan deposits resulting from nitro blue tetrazolium reduction and occurred in nuclei as well as cytoplasm. These findings suggest that CYP2A5 contributes to the superoxide production and 8-hydroxydeoxyguanosine formation, although reactive oxygen species from an unknown source in the hepatocytes leading to CYP2A5 induction or coincidental occurrence of these events are also possibilities. Three glutathione S-transferase isoforms, mGSTP1-1 (pi), mGSTA1-1 (YaYa), and mGSTA4-4, also showed striking increases evidencing major oxidative stress in these livers.
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PMID:Increased oxidative DNA damage and hepatocyte overexpression of specific cytochrome P450 isoforms in hepatitis of mice infected with Helicobacter hepaticus. 932 26

Mice naturally infected by Helicobacter hepaticus develop a chronic active hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer was used to examine the impact of bacterial infection on the hepatic expression and activity of enzymes involved in carcinogen bioactivation (phase I enzymes) and detoxification (phase II enzymes). No major differences in total cytochrome P450 (CYP) content were found between control and infected mice during the course of the study. The most striking modulations of individual isoenzymes were the increases in immunohistochemical staining observed for CYP1A and CYP2A5 in relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged over 12 months was confirmed by the observed increases in coumarin 7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an indicator for superoxide formation, demonstrated that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase II enzymes, an enhancement of glutathione S-transferase (GST) activities, related to the disease process, was observed in infected mice. An age-specific increase of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression was also demonstrated by immunohistochemical staining. In contrast, catalase and glutathione-peroxidase activities, as well as reduced glutathione content were decreased in the early stages of disease (3-9 months) in infected mice compared to age-matched control mice. Overall, these results suggest that alterations in CYP and GST expression may contribute to the aetiology of tumour incidence due to H. hepaticus infection via production of reactive oxygen species.
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PMID:Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus. 939 19

Arsenicals are epidemiologically significant chemicals in relation to induction of liver cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenicals in mammals, in a rat liver carcinogenesis model. In experiment 1, glutathione-S-transferase placental form (GST-P)-positive foci, putative preneoplastic lesions, were employed as endpoints of a liver medium-term bioassay for carcinogens (Ito test). Starting 2 weeks after initiation with diethylnitrosamine, male F344 rats were treated with 0, 25, 50 or 100 ppm of DMAA in the drinking water for 6 weeks. All animals underwent two-thirds partial hepatectomy at week 3 after initiation. Examination of liver sections after termination at 8 weeks revealed dose-dependent increases in the numbers and areas of GST-P-positive foci in DMAA-treated rats as compared with controls. In experiment 2, ornithine decarboxylase activity, which is a biomarker of cell proliferation, was found to be significantly increased in the livers of rats treated with DMAA. In experiment 3, formation of 8-hydroxydeoxyguanosine, which is a marker of oxygen radical-mediated DNA damage, was significantly increased after administration of DMAA. These results indicate that DMAA has the potential to promote rat liver carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals.
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PMID:Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver. 947 32

Extracts of Emblica officinalis (EO), Phyllanthus amarus (P. amarus) and Picrorrhiza kurroa (P. kurroa) significantly inhibited hepatocarcinogenesis induced by N-nitrosodiethylamine (NDEA) in a dose dependent manner. The anticarcinogenic activity of these extracts were evaluated by their effect on tumour incidence, levels of carcinogen metabolizing enzymes, levels of liver cancer markers and liver injury markers. Animals treated with NDEA alone showed 100% tumour incidence and significantly elevated tissue levels of drug metabolizing enzymes such as glutathione S-transferase (GST) and aniline hydroxylase (AH). Treatment of extracts significantly reduced these levels. Levels of gamma-glutamyl transpeptidase (GGT) were also found to be elevated both in serum and tissues of tumour bearing animals, while they were significantly reduced in the treated group. Similar reduction was seen in tissue levels of reduced glutathione. Serum levels of lipid peroxide (LPO), alkaline phosphatase (ALP) and glutamate pyruvate transaminase (OPT), which are markers of liver injury, were also elevated. Morphology of liver tissue and levels of marker enzymes indicated that these extracts offered protection against chemical carcinogenesis.
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PMID:Effect of Emblica officinalis, Phyllanthus amarus and Picrorrhiza kurroa on N-nitrosodiethylamine induced hepatocarcinogenesis. 1021 33

We investigated the expression of the drug resistance-related genes, multidrug resistance gene 1 (MDR1), multidrug resistance associated protein gene (MRP), and the DNA topoisomerase IIalpha, DNA topoisomerase IIbeta, and glutathione-S-transferase pi gene (GST-pi) in three human hepatoma cell lines (HepG 2, HuH 7, SK-Hep-1) with or without drug treatment with interferon-alpha (IFN-alpha) and cisplatin (CDDP), by a reverse transcription-polymerase chain reaction (RT-PCR) method and a competitive PCR method. The signals of the MDR1, MRP, topoisomerase IIalpha, and topoisomerase IIbeta genes in HepG2 were weakened when IFN-alpha was added to CDDP. In SK-Hep-1, the administration of CDDP alone increased the signals of MDR1 while the addition of IFN-alpha decreased the signals, and the signals of GST-pi were decreased by IFN-alpha plus CDDP. In summary, our results concerning the expression of drug resistance-related genes in three human hepatoma cell lines demonstrate that IFN-alpha may modulate the mechanism of resistance to CDDP in liver cancer.
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PMID:Interferon-alpha modulates resistance to cisplatin in three human hepatoma cell lines. 1043 11

We investigated whether changes in apoptosis and cell proliferation induced by starvation and refeeding in rat liver may contribute to the initiation mechanism of liver cancer by 20 mg/kg of diethylnitrosamine (DENA). Rats were starved for 4 d, then refed and given 20 mg/kg of DENA after 1 d of refeeding. Rat livers were examined before and after DENA treatment to measure DNA loss and synthesis, the number of the placental form of glutathione S-transferase (P-GST) positive cells and their turnover. Four days of starvation depressed cell replication, as indicated by the labeling index (LI), and induced apoptosis, as shown by the decay of total DNA radioactivity and apoptotic index (AI, TUNEL technique). After 1 d of refeeding, AI significantly decreased and LI remained low, indicating that a high percentage of S phase cells was not required for the DNA damage due to 20 mg/kg of DENA. DENA induced apoptosis and the AI after 20 mg/kg of DENA was 3% in refed rats vs. 1% in fully-fed rats 5 d after DENA (P </= 0.05). Putative-initiated P-GST-positive hepatocytes appeared after administration of 20 mg/kg in refed rats, and they showed a higher LI (6%) than the surrounding P-GST-negative cells 3 d after DENA (LI = 2%; P </= 0.01), while very few P-GST-positive cells were found in fully-fed rats. These data indicate that starvation-induced cell loss and the subsequent refeeding trigger cell proliferation that gives a selective advantage to the cells initiated by 20 mg/kg of DENA to grow in the livers of refed rats.
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PMID:Apoptosis and cell proliferation are involved in the initiation of liver carcinogenesis by a subnecrogenic dose of diethylnitrosamine in refed rats. 1061 75

We evaluated the effects of angiogenesis inhibitor, TNP-470, on hepatocellular carcinoma (HCCs) induced by a choline-deficient L-amino acid defined (CDAA) diet in rats. Male Fisher 344 rats were fed CDAA for 68 weeks. Rats were treated by subcutaneous injection of TNP-470 (15 mg/kg) or saline (control) three times per week from 53 to 68 weeks. At the end of the experiment, we determined the frequency and size of HCCs and glutathione S-transferase placental form (GSTP)-positive lesions, histology of liver cirrhosis, liver function, and liver weight per body weight. We also determined, using histologic and immunohistochemical semiquantification analyses, the degree of vascularity, apoptosis and proliferation in HCC and adjacent tissues. Treatment with TNP-470 resulted in a reduction of the size and frequency of HCC compared to untreated rats. However, TNP-470 did not influence the histology of liver cirrhosis and liver function. The liver weight per body weight of TNP-470-treated rats was slightly heavier in comparison with that of the controls. Treatment with TNP-470 significantly reduced tumor vascularity relative to the controls. There were no significant differences in the Ki-67 labeling index of HCCs between TNP-470 treated and control rats. The frequency of apoptotic hepatoma cells in TNP-470-treated rats was higher than in control rats. Our results indicate that TNP-470 suppresses the progression of CDAA-induced HCCs in rats through inhibition of angiogenesis, and suggest that TNP-470 might be useful clinically for HCCs.
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PMID:Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats. 1063 83

DRH strain rats were established by inbreeding a closed colony of Donryu rats continuously fed the chemical hepatocarcinogen 3'-methyl-4-dimethylaminoazobenzene for over 10 years. They are highly resistant to chemical induction of liver cancer and preneoplastic lesions. We studied the genetic basis of DRH resistance to preneoplastic lesions by analyzing 108 (F344 x DRH)F2 male rats fed 3'-methyl-4-dimethylaminoazobenzene for 7 weeks. Five parameters of preneoplastic liver lesions were selected for quantitative analysis: (a) number of glutathione S-transferase placental form-positive foci per unit area of liver section; (b) percentage area occupied by the foci; (c) average size of foci; (d) glutathione S-transferase placental form mRNA level; and (e) gamma-glutamyltranspeptidase mRNA level. Furthermore, O6-methylguanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor mRNA levels were quantified. Composite interval mapping analysis showed that there were two remarkably significant clusters of quantitative trait loci affecting preneoplastic liver lesions on chromosomes 1 and 4. These clusters were designated collectively as Drh1 and Drh2, respectively. The functions of the recessive DRH allele of Drh1 and the semidominant DRH allele of Drh2 were to suppress the phenotypes of precancerous lesions. Each cluster showed two to three subpeaks in linkage likelihood plots, suggesting the presence of several closely linked quantitative trait loci affecting preneoplastic lesions. Possible candidate genes at each locus will be discussed. Expression of O6-methylguanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor did not affect DRH resistance to hepatocarcinogenesis, although they were polymorphic between DRH and F344 rats.
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PMID:Genetic resistance to chemical carcinogen-induced preneoplastic hepatic lesions in DRH strain rats. 1085 Apr 31

The hepatitis B virus protein HBx has been implicated in the development of liver cancer. It has been shown that the HBx protein is able to bind to single-stranded DNA in a specific manner. This DNA binding activity might be relevant for HBx oncogene character. To study the HBx interaction with nucleic acids in more detail we expressed full-length HBx as well as several N- and C-terminally truncated HBx proteins as 6xHis and GST-fusions in E. coli. Using a gel shift assay, we were able to demonstrate that all of the truncated HBx proteins have the ability to bind to an AU-rich RNA. The affinity of GST-HBx #3 (residues 80-142) was an order of magnitude higher than that of GST-HBx #2 (residues 5-79), indicating that a high affinity RNA binding site is located in HBx C-terminal half. AUF1 is the protein ligand that binds to AU-rich RNA regions present in certain proto-oncogene mRNAs and causes their rapid degradation. By a competitive binding experiment of AUF1 and HBx to the AU-rich RNA oligonucleotide, we show that HBx is able to displace AUF1 from its binding site on the RNA oligonucleotide. This new aspect of HBx function is discussed in the context of cellular transformation.
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PMID:Expression of deletion mutants of the hepatitis B virus protein HBx in E. coli and characterization of their RNA binding activities. 1122 75


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