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)

Glutathione transferase P (GST-P; glutathione transferase, EC 2.5.1.18) is known to be specifically expressed at high levels in precancerous lesions and in hepatocellular carcinomas from a very early phase of chemically induced hepatocarcinogenesis in the rat. The almost invariable occurrence of this phenotype in these lesions strongly suggests a mechanism by which GST-P gene is activated together with a crucial transforming gene of liver cells. To distinguish the two alternative possibilities--either the GST-P gene is coactivated with a closely located transforming gene by a cis mechanism or it is activated in trans by a common trans-acting factor--we carried out carcinogenesis experiments using transgenic rats harboring the bacterial chloramphenicol acetyltransferase reporter gene ligated to the upstream regulatory sequence of the GST-P gene. In each of three independent lines tested, liver foci and nodules produced by chemical carcinogens (Solt-Farber procedure) were found to express high levels of chloramphenicol acetyltransferase activity, indicating clearly that the GST-P gene is activated by a trans mechanism during hepatocarcinogenesis.
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PMID:Trans-activation of glutathione transferase P gene during chemical hepatocarcinogenesis of the rat. 844 29

Glutathione transferase P (GST-P) is specifically induced in rat liver and kidney by lead cation. The increase of GST-P mRNA after lead administration is blocked by actinomycin D, suggesting that GST-P production by lead is regulated at the transcriptional level. To further determine which part of the flanking region of the GST-P gene has the lead-responsive cis-element in vivo, we utilized transgenic rats with five different constructs having GST-P and/or chloramphenicol acetyl-transferase coding sequence. We studied the effect of lead on these transgenic rats and on transfected NRK (normal rat kidney) cells and found that GST-P induction by lead is indeed regulated at the transcriptional level and that the GST-P enhancer I (GPEI) enhancer is an essential cis-element required for the activation of the GST-P gene by lead. GPEI consists of two AP-1 (c-Jun/c-Fos heterodimer) site-like sequences that are palindromically arranged and can bind AP-1, c-jun mRNA in the liver increased after lead administration and GST-P, and c-Jun had patchy expression in the same hepatocytes 24 h after lead exposure. These results suggest that activation of the GST-P gene by lead is mediated in major part by enhancer GPEI and that AP-1 may be involved at least partially. GPEI has been shown to have essential sequence information for the trans-activation of the GST-P gene during chemical hepatocarcinogenesis of the rat (Morimura, S., Suzuki, T., Hochi, S., Yuki, A., Nomura, K., Kitagawa, T., Nagatsu, I., Imagawa, M., and Muramatsu, M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2065-2068; Suzuki, T., Imagawa, M., Hirabayashi, M., Yuki, A., Hisatake, K., Nomura, K., Kitagawa, T., and Muramatsu, M. (1995) Cancer Res. 55, 2651-2655). The present study establishes that the same enhancer element does operate in the activation of the GST-P gene by lead regardless of the trans-activators involved.
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PMID:Activation of glutathione transferase P gene by lead requires glutathione transferase P enhancer I. 857 62

Glutathione transferase (GST, EC 2.5.1.18) P1-1 was strongly inhibited by captan and captafol in a time- and concentration-dependent manner. The IC50 values for captan and captafol were 5.8 microM and 1.5 microM, respectively. Time-course inactivation of GSTP1-1 by two pesticides was prevented by 3 microM of hexyl-glutathione, but not by methylglutathione. The fact that the inactivated enzyme recovered all the 5,5'-dithiobis(2-nitrobenzoic acid) titrable thiol groups, with concomitant recovery of all its original activity after treatment with 100 microM dithiothreitol, suggested that captan and captafol were able to induce the formation of disulfide bonds. That the inactivation of GSTP1-1 by captan and captafol involves the formation of disulfide bonds between the four cysteinil groups of the enzymes was confirmed by the SDS-PAGE experiments on nondenaturant conditions. In fact, on SDS-PAGE, GSTP1-1 as well as the cys47ala, cys101ala, and cys47ala/cys101ala GSTP1-1 mutants treated with captan and captafol showed several extra bands, with apparent molecular masses higher and lower than the molecular mass of native GSTP1-1 (23.5 kDa), indicating that both intra- and inter-subunit disulfide bonds were formed. These extra bands returned to the native 23.5 kDa band with concomitant restoration of activity when treated with dithiothreitol.
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PMID:Interaction of glutathione transferase P1-1 with captan and captafol. 867 7

Glutathione transferase (GST) from octopus hepatopancreas was rapidly inactivated by micromolar concentration of Cu(II) in the presence of ascorbate at neutral pH and 0 degree C. Omitting the metal ion or ascorbate, or replacing the Cu(II) with Fe(II) did not result in any inactivation. Glutathione or the conjugation product of glutathione and 1-chloro-2,4-dinitrobenzene offered complete protection of the enzyme from Cu(II)-induced inactivation. 1-Chloro-2,4-dinitrobenzene, however, did not provide any protection. The inactivation was time and Cu(II) concentration dependent. The dependence of inactivation rate on Cu(II) concentration displayed saturation kinetics, which suggests that the inactivation occurs in two steps with Cu(II) binding with the enzyme first (KdCu = 260 microM), then the locally generated free radicals modify the essential amino acid residues in the active center, which results in enzyme inactivation. The Cu(II)-ascorbate system is, thus, an affinity reagent for the octopus GST. The enzyme inactivation was demonstrated to be followed by protein cleavage. Native octopus GST has a subunit M(r) of 24,000. The inactivated enzyme was cleaved at the C-terminal domain (domain II) of the enzyme molecule and resulted in the formation of peptide fragment of M(r) 15,300, which has the identical N-terminal amino acid sequence as the native enzyme. The other half of the peptide with M(r) approximately 7700 was visible in the gels only after silver staining, which also revealed a minor cleavage site, also located at the domain II, to produce peptide fragments of M(r) approximately 11,300 and 8300. The oxygen carrier molecule in the cephalopods' blood is the copper-containing hemocyanin, which during turnover will release Cu(II). Our results indicate that Cu(II) catalyzes a site-specific oxidation of the essential amino acid residues at the C-terminus of GST causing enzyme inactivation. The modified-enzyme is then affinity cleaved at the putative metal binding site. The ability of octopus GST to bind with free Cu(II) may have important biological implications to enable cephalopods to avoid copper-induced cellular toxicity.
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PMID:Metal-catalyzed oxidation and cleavage of octopus glutathione transferase by the Cu(II)-ascorbate system. 893 81

Fibroblasts from an individual with 5-oxoprolinuria are deficient in glutathione (GSH) as compared to cells from a healthy sibling. Glutathione transferase (GST) levels also differ for some isoenzymes: GSH deficient cells have more GST A1-1, but lack GST M1-1. However, the contents of the quantitatively dominating isoenzyme GST P1-1 show no significant difference. While there is equal sensitivity to ultaviolet irradiation (UV), the GSH deficient cells are more sensitive to cisplatin, carboplatin and melphalan. Depletion of GSH with buthionine sulfoximine sensitizes the normal fibroblasts to these drugs. Only slightly more cisplatin-induced DNA cross-links are detected in the GSH deficient cells, and there is no difference in the removal of DNA cross-links. Similar amounts of DNA strand breaks are seen in normal and GSH deficient cells after UV exposure, but there is a reduced rates of resealing of strand breaks in GSH deficient cells. The main conclusion from the studies of these fibroblasts is that GSH plays a significant role in the cellular resistance to cytostatic drugs such as platinum compounds and melphalan.
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PMID:Increased cisplatin sensitivity of human fibroblasts from a subject with inherent glutathione deficiency. 893 14

Glutathione transferase (GST)-catalysed S-nitrosoglutathione (GSNO) formation from alkyl nitrites was determined with the homodimers 1-1, 2-2, 3-3, and 4-4 isolated from rat liver. The 4-4 isoform showed a high specificity for the alkyl nitrites. Total GST activities were studied in homogenates from different organs. The liver showed highest GST activity both with amyl nitrite and with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate, the activity ratio of amyl nitrite over CDNB being 3.8. In lung and heart, these ratios were 6.2 and 5.7, respectively, indicating a selectivity of these organs for alkyl nitrite metabolism and GSNO formation.
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PMID:Subunit specificity and organ distribution of glutathione transferase-catalysed S-nitrosoglutathione formation from alkyl nitrites in the rat. 896 71

Effects of continuous feeding flavonoids (flavone, flavanone, and tangeretin) on drug-metabolizing enzymes in rat liver were investigated to ascertain how long feeding is required to reach maximal induction and to determine whether maximal induction is maintained for a long period of feeding. In the first experiment rats received a diet containing 10 mmol flavonoid/kg dry matter for 4, 8, 16, or 32 d. The second experiment was designed to examine the time course for induction during the first 4 d. The kinetics of induction depended on the chemical structure of the flavonoid and was different from one enzyme to another. Flavone increased P450 1A and P450 2B apoproteins and stimulated many enzyme activities. A significant increase of P450 1A1/2 proteins, ethoxyresorufin O-deethylase (EROD), and methoxyresorufin O-demethylase (MROD) activities occurred as early as 6 h after the first administration, and a gradual increase was observed up to 4 d of feeding. P450 2B1/2 proteins and pentoxyresorufin O-depentylase (PROD) activity were also increased but after a lag period when compared with P450 1A1/2 proteins. EROD and MROD activities declined after 4 d, whereas PROD activity remained steady during 32 d of flavone feeding. Glutathione transferase (GST) and p-nitrophenol UDP-glucuronosyl transferase (UGT) activities were also increased. The maximal induction was reached by 4 d of feeding for UGT and after a longer duration of feeding (16 d) for GST. Flavanone treatment induced mostly P450 2B1/2 proteins and PROD, GST, and UGT activites. After 4 d of feeding, P450 2B1/2 proteins and PROD activity declined whereas GST and UGT activities remained steady. Tangeretin treatment produced changes similar to flavone but of lesser magnitude and after a longer delay.
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PMID:Time course of induction of rat hepatic drug-metabolizing enzyme activities following dietary administration of flavonoids. 896 9

Glutathione transferase (GSTs) have been shown to be overexpressed in a number of tumor cell lines selected for resistance to chemotherapeutic drugs and have been implicated in some studies of clinical specimens. In tumor cell lines selected for resistance to chemicals that alkylate DNA, the isoform most frequently overexpressed is GST-Yc, a member of the alpha class GSTs. To date, two variations of the cDNA designated Yc1 with subtle differences have been described, and Yc2 is shown to be clearly distinct. Transfection of a Yc1 cDNA constitutively expressed in rat liver into rat mammary cancer cells confers resistance to alkylators, however, to a lesser extent than is observed in the cells selected for resistance. It has therefore been widely suggested that the GST that is overexpressed in selected resistant cells represents a distinct and novel isoform. We have previously described a rat mammary carcinoma cell line (MLNr) that is resistant to alkylating agents, and overexpresses a GST with characteristics similar to GST-Yc1 and not Yc2. It has many features common to the several other GST-Yc overexpressing alkylator resistant cell lines. We have cloned the specific Yc cDNA overexpressed in MLNr and analyzed it in detail and found that it is identical to one of the previously reported Yc1 cDNAs, suggesting that there is no additional Yc gene specifically induced by nitrogen mustards. Another hypothesis to explain the difference in the level of resistance in selected versus GST-Yc transfected cells is the lack of concurrent increased glutathione (GSH) in the transfectants, which is a common feature in the selected resistant cells. Experiments in which we modulated GSH levels suggest that this is not likely. These studies add to our speculation that other mechanisms may be involved in alkylator resistance.
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PMID:Identification of the Yc1 glutathione S-transferase mRNA as the overexpressed species in a nitrogen mustard-resistant rat mammary carcinoma cell line. 941 83

Glutathione transferase was purified from Ochrobactrum anthropi and its N-terminal sequence was determined to be MKLYYKVGACSLAPHIILSEAGLPY. The apparent molecular mass of the protein (24 kDa) was determined by SDS-polyacrylamide gel electrophoresis analysis. The amino acid sequence obtained showed similarities with known bacterial glutathione transferases in the range of 72-64%. Immunoblotting experiments performed with antisera raised against glutathione transferase from O. anthropi did not show cross-reactivity with two bacterial glutathione transferases belonging to Serratia marcescens and Proteus mirabilis.
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PMID:Purification and characterization of a novel glutathione transferase from Ochrobactrum anthropi. 949 16

The Mexican axolotl (Ambystoma mexicanum) is a facultative neotene which rarely undergoes metamorphosis in the wild. We now report for the first time a dramatic increase in the expression of HoxA5 in axolotl hearts as determined by RT-PCR and in situ hybridization analyses during spontaneous metamorphosis. The Mexican axolotl has a naturally occurring mutation called gene c which allows hearts in homozygous (c/c) embryos to form but never to beat. RT-PCR analysis has not shown any significant differences of HoxA5 expression in normal and mutant hearts. The predicted open reading frame of our already published partial cDNA clone of HoxA5 was confirmed by expressing it as a fusion protein with Glutathione transferase (GST fusion protein). Phylogenetic analysis with the deduced amino acid sequence of the isolated cDNA of the axolotl homolog of the murine HoxA5 shows that the axolotl sequence clusters more closely with the human and mouse HoxA5 homologs than with axolotl sequence. Western blot analysis revealed that anti-mouse HoxA5 antibody recognizes the axolotl HoxA5 protein.
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PMID:The heart of metamorphosing Mexican axolotl but not that of the cardiac mutant is associated with the upregulation of Hox A5. 958 86


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