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)

The niaD and niiA genes of Aspergillus nidulans, which code, respectively, for nitrate and nitrite reductases, are divergently transcribed, and their ATGs are separated by 1,200 bp. The genes are under the control of the positively acting NirA transcription factor, which mediates nitrate induction. The DNA binding domain of NirA was expressed as a fusion protein with the glutathione S-transferase of Schistosoma japonicum. Gel shift and footprint experiments have shown that in the intergenic region there are four binding sites for the NirA transcription factor. These sites can be represented by the nonpalindromic consensus 5'CTCCGHGG3'. Making use of a bidirectional expression vector, we have analyzed the role of each of the sites in niaD and niiA expression. The sites were numbered from the niiA side. It appeared that site 1 is necessary for the inducibility of niiA only, while sites 2, 3, and to a lesser extent 4 (which is nearer to and strongly affects niaD) act bidirectionally. The results also suggest that of the 10 binding sites for the AreA protein, which mediates nitrogen metabolite repression, those which are centrally located are physiologically important. The insertion of an unrelated upstream activating sequence into the intergenic region strongly affected the expression of both genes, irrespective of the orientation in which the element was inserted.
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PMID:The intergenic region between the divergently transcribed niiA and niaD genes of Aspergillus nidulans contains multiple NirA binding sites which act bidirectionally. 756 20

Hepatocarcinogenic aromatic amines such as 4-aminoazobenzene derivatives and heterocyclic aromatic amines of cooked food origin were found to be liver-selective cytochrome P450IAZ (CYP1A2) inducers. Each aromatic amine showed different species-specificity among rodent experimental animals in terms of the extent of P450 induction. Carcinogenic susceptibility of an animal to the amine was well correlated with the activity and/or inducibility of CYP1A2 in the animals in the early initiation phase of the carcinogenesis. In hyperplastic nodules of rat liver, expression and induction of CYP1A2 as suppressed, especially in the placental form of glutathione S-transferase-positive foci. Despite the decrease of P450s including CYP1A2 in the rat liver bearing hyperplastic nodules. DNA adducts formed by a carcinogenic aromatic amine increased, as compared to the controls, suggesting that the activity of DNA repair enzyme(s) for the amine-derived DNA adducts might decrease in the hyperplastic nodules of rat liver. Treatment of rats with lead nitrate revealed a pattern of P450 expression in the liver similar to that observed with rats bearing hyperplastic nodules. These findings may provide valuable information on the roles of P450s in carcinogenic susceptibility of animals to aromatic amines and in the carcinogenic process.
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PMID:Induction of cytochrome P450 isoforms by carcinogenic aromatic amines and carcinogenic susceptibility of rodent animals. 758 95

1. The metabolism of a nitrate ester-substituted dihydropyridine derivative (NND) in vitro was characterized with rabbit hepatic microsomes and cytosol. 2. Denitration activity was located in both the microsomal and cytosolic fractions, whereas oxidation to the pyridine analogue was solely located in the microsomal fraction. 3. Oxidation to the pyridine analogue required NADPH and was inhibited by carbon monoxide, miconazole and SKF-525A, suggesting that oxidation was catalysed by P450. 4. Denitration activity in the microsomes required either NADPH or GSH. Together with these results, responses to various inhibitors indicate participation of both P450 and glutathione S-transferase (GST). 5. Denitration activity in cytosol was activated by glutathione (GSH), and by dithiothreitol (DTT) to a greater extent. GSH-dependent denitration was inhibited by S-hexyl GSH, an inhibitor of GST, but DTT-dependent denitration was not. Moreover, the formation patterns of the mono-denitrated metabolites, M1 and M2, were shown to be different in each incubation condition. 6. These results suggest that the denitration of NND in cytosol could be catalysed by a GSH-independent enzyme as well as the GSH-dependent enzyme, GST.
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PMID:Metabolism of a nitrate ester, dihydropyridine derivative in rabbit hepatic microsomes and cytosol. 761 54

The denitration of organic nitrate esters in rabbit hepatic cytosol was characterized. Sephadex G-200 chromatography of ammonium sulfate precipitate (40-80%) from hepatic cytosol demonstrated the presence of two distinct activities (peak I and peak II) responsible for the denitration of nitroglycerin (NTG) and isosorbide dinitrate (ISDN). The denitration of peak I required dithiothreitol (DTT), but not glutathione (GSH), and was not inhibited by S-alkyl GSH, an inhibitor of glutathione S-transferase (GST). Whereas, the denitration activity of peak II was potentiated by GSH, and was inhibited by S-alkyl GSH. These results strongly suggest that the denitration of organic nitrate esters, such as NTG and ISDN, can be catalyzed by at least two enzymes, GSH-independent denitration (peak I) and the GSH-dependent denitration (peak II, GST), in rabbit hepatic cytosol. The denitration activity of peak I was inhibited by SH-modified reagent, indicating that free thiol(s) is (are) critical for expression of the denitration activity. Also, in rabbit vascular cytosol, the cofactor requirement for denitration and response to S-hexyl GSH suggest the participation of GSH-independent enzyme which is responsible for the denitration of organic nitrate esters.
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PMID:GSH-independent denitration of organic nitrate esters in rabbit hepatic and vascular cytosol. 767 Aug 47

Dichloromethane (DCM) is efficiently utilized as a carbon and energy source by aerobic, Gram-negative, facultative methylotrophic bacteria. It also serves as a sole carbon and energy source for a nitrate-respiring Hyphomicrobium sp. and for a strictly anaerobic co-culture of a DCM-fermenting bacterium and an acetogen. The first step of DCM utilization by methylotrophs is catalyzed by DCM dehalogenase which, in a glutathione-dependent substitution reaction, forms inorganic chloride and S-chloromethyl glutathione. This unstable intermediate decomposes to glutathione, inorganic chloride and formaldehyde, a central metabolite of methylotrophic growth. Genetic studies on DCM utilization are beginning to shed some light on questions pertaining to the evolution of DCM dehalogenases and on the regulation of DCM dehalogenase expression. DCM dehalogenase belongs to the glutathione S-transferase supergene family. Analysis of the amino acid sequences of two bacterial DCM dehalogenases reveals 56% identity, and comparison of these sequences to those of glutathione S-transferases indicates a closer relationship to class Theta eukaryotic glutathione S-transferases than to a number of bacterial glutathione S-transferases whose sequences have recently become available. dcmA, the structural gene of the highly substrate-inducible DCM dehalogenase, is carried in most DCM utilizing methylotrophs on large plasmids. In Methylobacterium sp. DM4 its expression is governed by dcmR, a regulatory gene located upstream of dcmA, dcmR encodes a trans-acting factor which negatively controls DCM dehalogenase formation at the transcriptional level. Our working model thus assumes that the dcmR product is a repressor which, in the absence of DCM, binds to the promoter region of dcmA and thereby inhibits initiation of transcription.
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PMID:Microbes, enzymes and genes involved in dichloromethane utilization. 776 35

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
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PMID:Mechanisms of action of nitrates. 787 67

Glutathione transferase P1-1, normally very low in adult rat liver, is induced by a single intravenous dose of lead nitrate. In this transient induction, there are at least three sites of regulation or control. These are transcription, post-transcription, and post-translation. The increase in transcription is evident both by nuclear run-off analysis and by measurement of mRNA levels. The other two sites of control were seen in actinomycin D-treated animals in which RNA synthesis was inhibited by over 80%. Treatment with actinomycin D increases the stability of the mRNA and also somehow inhibits the conversion of a glutathione transferase protein to an enzymatically active form. These three sites offer possibilities for the study of mechanisms of control for this interesting enzyme that may play a role in chemical carcinogenesis and in drug resistance.
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PMID:Multiple sites of control of glutathione S-transferase P1-1 in rat liver. 818 66

Male F344 rats were treated with lead nitrate and changes in the expression and induction of P450IA subfamily enzymes and a placental form of glutathione-S-transferase (GST-P) in the liver were assessed by means of a bacterial mutation test, immunoblotting with a monoclonal antibody reactive to P450IA1/IA2 and anti-GST-P sera and Northern blotting with P450IA2 cDNA as a probe. Treatment of rats with lead nitrate (20, 50 or 100 mumol/kg body wt) decreased P450IA2 mRNA and protein in the liver in the dose-dependent fashion and also decreased the microsomal activity for P450IA2-dependent mutagenization of aromatic amines. Pretreatment of rats with lead nitrate suppressed the inductions of both P450IA2 mRNA and protein by an inducer of P450IA subfamily enzymes in the liver. In addition, amount of the induced P450IA2 was decreased along with increase in that of the induced GST-P.
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PMID:Preferential inhibitions of hepatic P450IA2 expression and induction by lead nitrate in the rat. 850 93

An experiment was performed to investigate whether, during regression of the liver hyperplasia induced by a direct mitogen, apoptosis differentially affects replicated and non-replicated hepatocytes. After a single dose of the direct mitogen lead nitrate (LN), male Wistar rats were given repeated injections of tritiated thymidine, and were killed either 3 days (time of maximal hepatic DNA increase) or 15 days (complete regression of the hyperplasia) after mitogen treatment. Determination of liver DNA radioactivities and labelling indices (LIs) at the two time points revealed an approximately 40% loss in total liver DNA radioactivity, a 20% decrease in the specific activity of DNA, and a 20% reduction in the cell LI. Three days after LN administration 64% of the apoptotic bodies contained thymidine grains in their nuclear fragments. The results indicated that apoptosis affects both hepatocytes that replicated, and those that did not replicate, the former being slightly more sensitive. A second experiment was then performed to investigate whether and to what extent different types of cell death (apoptosis versus necrosis) influence the growth of hepatocytes initiated by a chemical carcinogen. Male Wistar rats were given a single dose of diethylnitrosamine, and 2 weeks thereafter either a single dose of LN, or a necrogenic dose of carbon tetrachloride (CCl4). Bromodeoxyuridine was next infused for 5 days, and some of the animals were killed at this time point, and others after an additional 3 weeks. Administration of CCl4 resulted in an increase in both the average size and the percentage area occupied by placental glutathione S-transferase-positive lesions. In contrast, administration of lead nitrate resulted in a strong reduction (50%) in the number of positive lesions with no remarkable change in the percentage area occupied by them. These differential effects occurred even though comparable LIs were observed in rats treated with the two agents. The results suggest that lead nitrate leads to a loss of initiated hepatocytes, due to the apoptosis that occurs during regression of the LN-induced hyperplasia.
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PMID:Effects of cell proliferation and cell death (apoptosis and necrosis) on the early stages of rat hepatocarcinogenesis. 863 Nov 22

Male F344 rats were pretreated with lead nitrate, nickel chloride, cobalt chloride or cadmium chloride, and their effects on the induction of cytochrome P450 (CYP) enzymes, mainly CYP1A2 enzyme, with 2-methoxy-4-aminoazobenzene (2-MeO-AAB) in the livers were comparatively examined by enzymatical, immunochemical, and molecular biological methods. When rats were pretreated with each ionic metal, the total CYP amount in the liver microsomes decreased, as compared with that of rats treated with 2-MeO-AAB alone. However, among the ionic metals used only lead reduced the levels of the mRNA and protein of CYP1A2 induced with 2-MeO-AAB in the rat liver, and decreased the microsomal activity (per CYP) for CYP1A2-mediated mutagenesis. Furthermore, ionic lead, but not other ionic metals, showed an ability to induce a placental form of glutathione S-transferase (GST-P). The level of CYP1A2 induced with 2-MeO-AAB was decreased along with increase in that of the induced GST-P.
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PMID:Ionic lead, but not other ionic metals (Ni2+, Co2+ and Cd2+), suppresses 2-methoxy-4-aminoazobenzene-mediated cytochrome P450IA2 (CYP1A2) induction in rat liver. 884 8


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