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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.
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PMID:Chlorambucil in chronic lymphocytic leukemia: mechanism of action. 903 Oct 99

Rats treated with quinoline, and to a lesser extent, isoquinoline (75 mg/kg, daily for 3 days) showed induction of phase II drug metabolizing enzyme activities without inducing either cytochrome P450 concentration or CYP1A-, CYP2B-, CYP2E-, and CYP3A-selective activities. Elevations of UDP-glucuronosyltransferase activities towards 4-nitrophenol, 1-naphthol, and morphine elicited by quinoline (1.9- to 2.7-fold), were greater than those elicited by isoquinoline (1.4- to 1.8-fold). UDP-glucuronosyltransferase activities towards estrone and testosterone were not increased by either compound. Microsomal epoxide hydrolase activity was increased only by quinoline (2.7-fold). NAD(P)H quinone oxidoreductase activity was increased 2-fold by quinoline and isoquinoline. Cytosolic glutathione S-transferase (GST) activity was increased similarly (approximately 20%) by both agents. Similar treatment of rats with either quinine (75 mg/kg) or chloroquine (150 mg/kg) increased 1-naphthol glucuronidation and GST (quinine only) activities. At 75 mg/kg, chloroquine did not affect any phase II enzyme activities but caused a minor elevation of a phase I enzyme, CYP1A; ascertained from an elevation of 7-ethoxyresorufin deethylase activity and a small hypsochromic shift to the absorbance maximum of the cytochrome P450 CO-complex. With quinoline and isoquinoline treatments (n = 14), the correlation coefficients (R) between microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine were 0.96 and 0.92 respectively, suggesting a highly coordinated induction. The highest NAD(P)H quinone oxidoreductase correlations were with microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine (R approximately 0.78). Correlation coefficients between GST and microsomal epoxide hydrolase and NAD(P)H quinone oxidoreductase activities were approximately 0.49. Quinoline and isoquinoline, nitrogen heterocyclic analogs of naphthalene, join the list of simple nitrogen-containing polycyclic aromatic agents capable of selective induction of phase II drug metabolizing enzymes. The position of the single heterocyclic nitrogen atom in the bicyclic ring influences the magnitude and breadth of the induction response. The addition of bulky ring substituents (quinine, chloroquine) reduced the induction response.
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PMID:Selective induction of phase II drug metabolizing enzyme activities by quinolines and isoquinolines. 913 7

Hydroxylamine (HYAM, HONH2) and some of its derivatives are known to cause erythrotoxic effects both in vitro and in vivo. Previous studies have shown that the primary in vitro effect of HYAM and O-ethyl hydroxylamine (OEH) is methaemoglobin formation, leading to liberation of free radicals which cause lipid peroxidation, enzyme inhibitions and glutathione depletion. By contrast, N-substituted N,O-dimethyl hydroxylamine (NODMH), primarily induces impairment of glucose 6-phosphate dehydrogenase (G6PDH) and glutathione reductase (GR). The oxidative potency of HYAM and the O-derivative was larger than the potency of the N,O-derivative. This seemed to indicate that attachment of an alkyl group to the nitrogen atom of hydroxylamine leads to decreased reactivity. To achieve a better understanding of the structure activity relationship for hydroxylamines three methylated derivatives were tested: N-methyl hydroxylamine (NMH). N-dimethyl hydroxylamine (NDMH) and O-methyl hydroxylamine (OMH). We were also interested in the erythrotoxic potency of OMH which recently entered industrial production. Methaemoglobin formation, high release of lipid peroxidation products, inhibition of NADPH methaemoglobin reductase and glutathione S-transferase (GST) and depletion of total glutathione (GT) were seen for OMH. The reducing enzymes G6PDH and GR were not impaired by OMH. These findings for OMH are consistent with the proposed mechanism for O-derivatives. Since both the effects caused by OMH and its potency are comparable to those of HYAM and OEH this indicates that possible occupational exposure to this compound may be approached similarly to HYAM and OEH. NMH only inhibited G6PDH and GR activity, which is fully in accord with the proposed mechanism for N-substituted derivatives of HYAM. However, NDMH a double N-substituted compound, caused a strikingly different scheme of reactivity inhibition of G6PDH but not of GR, severe methaemoglobin formation, only little lipid peroxidation and some impairment of NADPH methaemoglobin reductase. This study confirms that O-derivatives of HYAM are potent haemoglobin oxidators, leading to other oxidative effects. The main effect was confirmed for single N-derivatives as inhibition of the two protective enzymes G6PDH and GR. However, the results for NDMH indicate that this simple classification of O-derivatives and N-derivatives has to be extended for double N-substituted compounds which give a mixture of effects.
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PMID:In vitro haematotoxic effects of three methylated hydroxylamines. 913 8

Rats were treated with nitrogen-containing phenanthrene (3,4-, 5,6-, or 7,8-benzoquinoline) or anthracene (acridine or quinacrine) derivatives at a dose of 75 mg/kg, daily for 3 days. The hepatic drug metabolizing enzyme response ranged from no induction (quinacrine) through low (5,6-benzoquinoline), intermediate (acridine), and high (3,4-benzoquinoline) magnitude increases of only phase II enzymes, to induction of both phase I and phase II enzymes (7,8-benzoquinoline). The phase I enzyme response of 7,8-benzoquinoline was an induction of CYP1A. All three benzoquinolines, but neither anthracene derivative, elevated NAD(P)H quinone oxidoreductase activity. A similar pattern but of lesser magnitude was seen with glutathione S-transferase activity. 3,4-Benzoquinoline was the only agent to significantly increase microsomal epoxide hydrolase activity (2,3-fold). Both 3,4- and 7,8-benzoquinoline increased UDP-glucuronosyltransferase activity toward 4-nitrophenol (40% and 70%, respectively), but only the 3,4-isomer increased activity toward morphine (75%), diclofenac (75%), and testosterone (23%), and only the 7,8-isomer increased activity toward chloramphenicol (105%). 3,4-Benzoquinoline elevated the hepatic mRNA concentration of UGT2B1 but not UGT1*6. Acridine treatment increased UDP-glucuronosyltransferase activity toward morphine (47%), 1-naphthol (28%), testosterone (19%), and estrone (19%). Quinacrine failed to elevate any UDP-glucuronosyltransferase activity and depressed activities toward testosterone and estrone by 20%. This study shows that some tricyclic aromatic compounds containing a single heterocyclic nitrogen atom have the potential for use as chemoprotective agents based upon their ability to selectively induce only phase II enzymes.
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PMID:Drug metabolizing enzyme induction by benzoquinolines, acridine, and quinacrine; tricyclic aromatic molecules containing a single heterocyclic nitrogen. 917 41

A subchronic rat study with paired-water control was conducted to resolve the question of whether monochloramine at 200 ppm in drinking water can cause reduced body weight gain and other changes observed in earlier investigations. Male Sprague-Dawley rats (93 +/- 5 g) were divided into three groups of 10 rats each: the treatment group was fed drinking water containing 200 ppm monochloramine, the control group was fed bicarbonate-buffered water ad libitum, and the paired-water control rats were given a daily volume of bicarbonate-buffered water equal to that consumed by the monochloramine treatment group. Compared to the control group, rats in the treatment group consumed an average of 42% less fluid and 16% less food over the 13-week treatment period and had 15-20% lower final body weight gain. Similar degrees of reduction in food consumption and body weight gain were observed in the paired-water rats. A decreased liver to body weight ratio occurred in the treatment and paired-water groups. Increased inorganic phosphate, albumin, total protein, and urea nitrogen were detected in sera from both the treatment group and the paired-water groups. The paired-water animals had lower levels of white blood cells and lymphocytes, while the paired-water and monochloramine-treated groups had reduced monocyte counts. Except for a slightly increased response to Con A observed in splenic lymphocytes of the monochloramine-treated rats (versus the paired-water), no significant changes were found in mitogen responsiveness to T cell, B cell, and B plus T cell mitogens or in splenic natural killer (NK) cell activities. There were no significant changes in serum levels of IgG, IgA, and IgM. The following biochemical parameters showed no significant variations among the three groups: serum thyroxin, liver phase I (PROD, EROD, and MROD) and phase II (UDPGT and GST) drug-metabolizing enzyme activities; serum and liver thiobarbituric acid-reactive substances (TBARS); bronchoalveolar lavage fluid protein and N-acetylgluosaminidase (NAGA) activity; and urinary ascorbic acid, protein, and NAGA activity. Histopathological examination revealed minimal to mild adaptive changes in the liver of the paired-water and monochloramine-treated rats and in the thyroid of the monochloramine-treated animals. No treatment-related cytological changes were found in red cells and bone marrow. The results indicate that the reduced body weight gain and the minor biochemical, hematological, immunological, and histopathological changes associated with subchronic exposure to 200 ppm monochloramine in drinking water (equivalent to an intake of 21.6 mg/kg/day) were largely related to the reduced water intake and food consumption and not caused by monochloramine.
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PMID:Effects of subchronic exposure of monochloramine in drinking water on male rats. 918 92

The pr1 gene of the entomopathogenic fungus Metarhizium anisopliae encodes a serine protease that is highly active towards the insect cuticle and whose synthesis is subject to both carbon and nitrogen repression. The pr1 promoter region was sequenced revealing the presence of putative CREA- and AREA-binding sites. In vitro bandshift experiments demonstrated that an Aspergillus nidulans GST-CREA fusion protein was capable of binding to two of the three putative CREA sites. Using a PCR-based strategy the M. anisopliae crr1 gene was identified; it encodes a putative C2H2-type DNA-binding protein with significant sequence similarity to A. nidulans CREA. Complementation experiments with an A. nidulans strain carrying creA204 demonstrated that CRR1 can partially substitute for CREA function.
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PMID:Carbon regulation of the cuticle-degrading enzyme PR1 from Metarhizium anisopliae may involve a trans-acting DNA-binding protein CRR1, a functional equivalent of the Aspergillus nidulans CREA protein. 921 95

Enzymes of the glutathione-dependent detoxification pathway (glutathione S-transferase and gamma-glutamyl-transpeptidase) were induced, and the glutathione pool was completely depleted by phenoxyacetic acid in Penicillium chrysogenum mycelia incubated for 15 h in a culture medium containing lactose as a carbon source and sodium glutamate as a nitrogen source. A significant increase in both the oxidised glutathione concentrations and the glutathione reductase activities were also observed. 1-Chloro-2,4-dinitrobenzene--a potent substrate and inducer of glutathione S-transferase-initiated very similar physiological changes but no beta-lactam production could be detected in this case. When (NH4)2HPO4 was used as a nitrogen source the penicillin biosynthesis was repressed and the induction of gamma-glutamyltranspeptidase by phenoxyacetic acid was hindered considerably.
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PMID:Phenoxyacetic acid induces glutathione-dependent detoxification and depletes the glutathione pool in Penicillium chrysogenum. 926 40

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

Geniposide is an iridoid glycoside extracted from the fruits of Gardenia jasminoides, which are used as a food colorant and as a traditional Chinese medicine for treatment of hepatic and inflammatory diseases. The effects of geniposide and G. jasminoides fruit crude extract on liver cytochrome P-450 (P-450)-dependent monooxygenases, glutathione and glutathione S-transferase were investigated using rats treated orally with the iridoid glycoside (0.1 g/kg body weight/day) or the fruit crude extract (2 g/kg/day) for 4 days. The treatments decreased serum urea nitrogen level but increased liver to body weight ratio, total hepatic glutathione content and hepatic cytosolic glutathione S-transferase activity. Treatments with geniposide and G. jasminoides decreased P-450 content, benzo[a]pyrene hydroxylation, 7-ethoxycoumarin O-deethylation, and erythromycin N-demethylation activities in liver microsomes without affecting aniline hydroxylation activity. The natural products had no effect on glutathione content and monooxygenase activities in kidney microsomes. Immunoblotting analyses of liver microsomal proteins using mouse monoclonal antibody 2-13-1 to rat P4503A1/2 revealed that geniposide and G. jasminoides crude extract decreased the intensity of a P4503A-immunorelated protein. Protein blots probed with mouse monoclonal antibody 1-12-3 to rat P4501A1 and rabbit polyclonal antibody against human P4502E1 showed that both treatments had little or no effect on P4501A and 2E proteins. The present findings demonstrate that geniposide from G. jasminoides has the ability to inhibit a P4503A monooxygenase and increase glutathione content in rat liver.
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PMID:Modulation of cytochrome P-450-dependent monooxygenases, glutathione and glutathione S-transferase in rat liver by geniposide from Gardenia jasminoides. 946 29

TER286 is a latent drug activated by human glutathione S-transferase (GST) isoforms P1-1 and A1-1 to produce a nitrogen mustard alkylating agent. M7609 human colon carcinoma, selected for resistance to doxorubicin, and MCF-7 human breast carcinoma, selected for resistance to cyclophosphamide, both showed increased sensitivity to TER286 over their parental lines in parallel with increased expression of GST P1-1. In primary human tumor clonogenic assays, the spectrum of cytotoxic activity observed for TER286 was both broad and unusual when compared to a variety of current drugs. In murine xenografts of M7609 engineered to have high, medium, or low GST P1-1, responses to TER286 were positively correlated with the level of P1-1. Cytotoxicity was also observed in several other cell culture and xenograft models. In xenografts of the MX-1 human breast carcinoma, tumor growth inhibition or regression was observed in nearly all of the animals treated with an aggressive regimen of five daily doses. This schedule resulted in a 24-h posttreatment decline in bone marrow progenitors to 60% of control and was no worse than for a single dose of TER286. These studies have motivated election of TER286 as a clinical candidate.
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PMID:Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase. 963 80


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