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)

The cytochrome P450 superfamily of enzymes play a central part in the metabolism of carcinogens and anti-cancer drugs. The expression, cellular localisation, and distribution of different forms of P450 and the functionally associated enzymes epoxide hydrolase and glutathione S-transferases have been investigated in oesophageal cancer and non-neoplastic oesophageal tissue using immunohistochemistry. Expression of the different enzymes was confined to epithelial cells in both non-neoplastic samples and tumour samples except the CYP3A was also identified in mast cells and glutathione S-transferase pi was present in chronic inflammatory cells. CYP1A was present in a small percentage of non-neoplastic samples but both CYP2C and CYP3A were absent. Epoxide hydrolase was present in half of the non-neoplastic samples and the different classes of glutathione S-transferase were present in a low number of samples. In carcinomas CYP1A, CYP3A, epoxide hydrolase, and glutathione S-transferase pi were expressed in at least 60% of samples. The expression of glutathione S-transferases alpha and mu were significantly less in adenocarcinoma compared with squamous carcinoma.
 ...
PMID:Cytochrome P450 expression in oesophageal cancer. 820 May 49

The influence of rats' long-term ethanol consumption on liver enzymes that could be involved in the biotransformation of benzo(a)pyrene [B(a)P] has been studied. Male and female Wistar rats received an increasing amount of ethanol in their drinking water up to 15% (w/v) in three weeks. The ethanol content was kept at a concentration of 15% for another three weeks. One group of rats also received B(a)P in the last week of the ethanol treatment. Livers were isolated, and microsomal and cytosolic fractions were prepared. In every enzyme measurement sex differences were observed. Long-term ethanol consumption induced P450, especially aniline 4-hydroxylase (P4502E1). However, testosterone 6 beta-hydroxylase (P4503A2 and P4502C13) in males and testosterone 12 beta-hydroxylase in females were decreased. The phase 2 enzymes glutathione S-transferase (subunit 1) and epoxide hydrolase were also decreased in their activity. Our results support the hypothesis that the effect of long-term ethanol consumption on B(a)P biotransformation as found in in vivo and in vitro studies, consisting of lowered formation of phenolic and diolic metabolites, is the result of a decrease of constitutive P450 isoenzymes.
 ...
PMID:Influence of long-term ethanol treatment on rat liver biotransformation enzymes. 821 87

In this report we describe the heterologous expression of glutathione S-transferase (GST) and cytochrome P450 reductase (Red) in E. coli and Salmonella typhimurium. The same expression vectors could be applied to both systems and high levels of catalytically active GST and Red were obtained. Interestingly the level of expression was invariably higher in S. typhimurium. The level of the alpha class GST being up to 20% of the total bacterial protein. A further advantage of the salmonella system is that strains were used which can be applied to mutagenicity tests. This system was validated by demonstrating increasing mutation frequency of halogenated hydrocarbons in strains expressing the GST and increased cytotoxicity of mitomycin C in cells expressing P450 reductase.
 ...
PMID:Heterologous expression of drug-metabolizing enzymes in cellular and whole animal models. 823 79

The alkylating agent BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] can be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes. While previous studies have identified a class mu glutathione S-transferase [rat transferase 4-4 (Yb2)] as a major catalyst of the cytosolic denitrosation reaction, the enzymatic catalysts of BCNU denitrosation in microsomal membranes have not been identified. In the present study, both NADPH and glutathione (GSH) were found to support BCNU denitrosation catalyzed by isolated rat liver microsomes. Treatment of rats with the microsomal enzyme inducers phenobarbital and dexamethasone increased NADPH-dependent liver microsomal BCNU denitrosation up to fivefold without major effect on the GSH-dependent denitrosation activity. Although the NADPH-dependent activity was fully inhibited by antibody to NADPH-P450 reductase, purified NADPH-P450 reductase catalyzed BCNU denitrosation at rates that could only account for approximately 2-3% of the microsomal activity. Other experiments, including selective inhibition of NADPH-dependent microsomal BCNU denitrosation by chemical and antibody inhibitors of cytochrome P450, competitive inhibition of P450-catalyzed cyclophosphamide and ifosfamide activation by BCNU, and reconstitution of the denitrosation reaction by purified P450 enzyme 2B1 (major phenobarbital-inducible P450 form), established an important role for cytochrome P450 in BCNU denitrosation. By contrast, GSH-dependent microsomal BCNU denitrosation was unaffected by cytochrome P450 inhibitors, but was inhibited, with varying degrees of selectivity, by the microsomal glutathione S-transferase inhibitors ethacrynic acid, bromosulfophthalein, and indomethacin. These studies establish that BCNU inactivation can be catalyzed by two independent microsomal enzyme systems and suggest that therapeutically useful improvements in BCNU antitumor activity might be achieved through differential inhibition of these enzyme systems in tumor as compared to extratumoral sites.
 ...
PMID:Denitrosation of the anti-cancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea catalyzed by microsomal glutathione S-transferase and cytochrome P450 monooxygenases. 827 24

1. The expression of P450 isoenzymes in foetal and neonatal hepatic microsomes was determined by measuring the metabolism of marker substrates and by studying the expression of P450 isoenzymes at the protein and mRNA level. 2. Monooxygenase activities were not measurable at day 10 of gestation, but shortly before birth (day 20 of gestation) and thereafter a surge in monooxygenase activities was observed using ethoxyresorufin, aniline, nitroanisole, aminopyrine, dimethylnitrosamine and aldrin as substrates. 3. In contrast, as early as day 10 of gestation, post oxidative drug metabolism was measurable, when assessed for reactions catalysed by UDP-glucuronyltransferase, glutathione S-transferase and epoxide hydrolase. 4. Microsomal proteins isolated from foetal/perinatal rats did not crossreact with antibodies raised to CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1, CYP3A1 and CYP4A1 at a protein loading of 3 micrograms total protein/well. 5. With the exception of CYP2E1 mRNA and CYP4A1 mRNA there was little evidence to suggest the expression of CYP1A1, CYP1A2 and CYP2A1 mRNA. 6. The mRNA of CYP2B1, CYP2C7 and CYP3A1 was not detectable in foetal/perinatal rat liver extracts at a loading rate of 10 micrograms total RNA. 7. Microsomal proteins isolated from neonatal rats crossreacted with antibodies raised to CYP2C6, CYP2E1, CYP3A1 and CYP4A1, albeit at varying intensities. 8. Concomitantly, CYP2A1, CYP2E1 and CYP4A1 mRNA transcripts were detectable in Northern blot hybridization experiments using neonatal rat liver RNA extracts.
 ...
PMID:Expression of P450 isoenzymes during rat liver organogenesis. 828 35

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), induces lung tumors in mice, rats, and hamsters. Phenethyl isothiocyanate (PEITC), which occurs as gluconasturtiin in cruciferous vegetables, is a potent inhibitor of NNK-induced carcinogenesis. The present study investigated the enzymatic basis for the bioactivation of NNK and the mechanisms of the inhibition of this process by dietary PEITC in mice. The apparent Km for the formation of keto aldehyde, keto alcohol, and NNK-N-oxide in lung microsomes was 4.9, 2.6, and 1.8 microM and, in liver microsomes, 5.5, 5.1, and 8.8 microM, respectively. Immunoinhibition studies suggested that cytochrome P450s (P450s) 2A1 and 2B1 or related forms are the major enzymes involved in the oxidative metabolism of NNK in mouse lung microsomes. When female A/J mice were fed diets containing 0, 1, or 3 mumol of PEITC/g of diet for 4 wk, the dietary PEITC had no significant effects on the food consumption and body weight of the mice. NNK oxidation in the lung microsomes of mice consuming the 1 or 3 mumol of PEITC/g of diet was decreased by 13 to 27% or 30 to 50%, respectively. In liver microsomes, whose NNK oxidative metabolism rates were about twice those of lung microsomes on a per mg of protein basis, the activities were decreased by 14 to 31% by the 3 mumol of PEITC/g of diet. The apparent Km remained unchanged, and the apparent Vmax decreased in the lung and liver microsomes of PEITC-fed mice, suggesting a noncompetitive nature of the inhibition. When added to the incubation mixture, PEITC decreased NNK metabolism in a concentration-dependent manner and exhibited a competitive inhibition with apparent Ki values of 51 to 93 nM. Dietary PEITC decreased the hepatic P450 content by 25%, but increased (2-fold) the O-dealkylase activities of 7-pentoxyresorufin (indicative of P450 2B1) and 7-ethoxyresorufin (indicative of P450 1A) in the liver microsomes of mice consuming the 3 mumol of PEITC/g of diet. The P450 2B level was increased in liver microsomes but slightly decreased in the lung microsomes. The p450 2E1 level was increased by dietary PEITC by 1.2- and 1.6-fold in the liver and lung microsomes, respectively. The activities of glutathione S-transferase and NAD(P)H-quinone oxidoreductase in liver and lung microsomes were not affected appreciably by the dietary PEITC treatment. The results suggest that chronic consumption of PEITC decreases the rate of metabolic activation of NNK by chemical inactivation and competitive inhibition of the enzyme(s) responsible for NNK oxidation.
 ...
PMID:Mechanisms of inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation in mouse by dietary phenethyl isothiocyanate. 832 38

To better understand drug and carcinogen metabolism pathways in head and neck squamous cell carcinoma we assayed the principal drug- and carcinogen-metabolizing enzyme systems in both tumors and their corresponding adjacent non-tumoral tissues. Cytochromes P450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase and glutathione S-transferases (GST-alpha, GST-mu, GST-pi) were assayed by immunoblotting. GST activity, total glutathione, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase and sulfatase, were determined by spectral assays. Results showed the absence of all probed cytochromes P450 in tumors and non-tumoral tissues, including P450 1A1/1A2 known to be involved in tobacco-related carcinogenesis. No statistical difference was noted between tumors and adjacent non-tumoral tissues for most enzymes studied (GST-alpha, GST-mu, GST-pi, GST activity, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase and sulfatase). However, total glutathione concentrations were significantly higher (P < 0.05) in tumors (47 +/- 20 nmol/mg protein) than in non-tumoral tissues (19 +/- 9). On the contrary, epoxide hydrolase was significantly less expressed in tumors (18 +/- 9 micrograms/mg protein) compared to corresponding non-tumoral tissues (37 +/- 9). These data provide new information concerning human head and neck cancer biology that could possibly have clinical implications.
 ...
PMID:Principal xenobiotic-metabolizing enzyme systems in human head and neck squamous cell carcinoma. 833 Mar 40

It is important to study the development of drug biotransformation enzymes, because from a pharmacological and therapeutic point of view these enzymes are responsible for eliminating most drugs. Their concentration at each age is critical when deciding the dose regimen, particularly in the neonates who are deficient or have very low levels of these enzymes. From a toxicological perspective, the role of these enzymes varies, with some of them being directly responsible for activation of certain chemicals to reactive intermediates with deleterious consequences to the animal. The time course of appearance of these enzymes throughout the life of the animal could be depicted from the study of their ontogeny and therefore the prediction of when the animal would be at risk should be possible. Experiments were designed to measure in vitro, the activity of drug-metabolizing enzymes in liver, lung and kidney of newborn, 1-week-, 4-week and 6-week-old and adult goats. The microsomal monoxygenase activities were measured utilizing substrates designed to characterize the development of the cytochrome P450 (P450). For phase II enzymes, the activity of UDP-glucuronyltransferase towards 1-naphthol and p-nitrophenol was measured in addition to the cytosolic glutathione S-transferase activity towards, 1,2-dichloro 3-nitrobenzene. The results indicated that the newborn goat tissues exhibited very low activity of drug-metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In general, the development of the mono-oxygenase activities followed the same pattern as the overall P450. The UDP-glucuronyltransferase activity towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacologic implication of the development of these enzyme activities are discussed.
 ...
PMID:The postnatal development of drug-metabolizing enzymes in hepatic, pulmonary and renal tissues of the goat. 834 65

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
 ...
PMID:Metabolic polymorphisms. 836 90

In a concerted analysis of the genes encoding three mouse steroid hydroxylases, we identified and characterized a transcriptional regulatory protein, designated steroidogenic factor 1 (SF-1), that contributes to the coordinate expression in adrenocortical cells. SF-1, an orphan member of the nuclear receptor family, binds to PyCAAGGPyCPu motifs upstream of the steroid hydroxylases to regulate their expression. In the present study, we extend these findings by examining the role of SF-1 in regulation of the rat P450 aromatase gene in gonadal tissues. The 5'-flanking region of the rat aromatase gene was isolated by a polymerase chain reaction-based approach, using primers corresponding to the 5'- and 3'-ends of a published aromatase sequence. DNA sequence analysis revealed three differences between our sequence and the previously published sequence, including a 44-base pair (bp) insertion. Moreover, the transcription initiation site, as determined by primer extension analysis, differed from that previously proposed. The new transcription initiation site is located 23 bp 3' of a putative TATA box. When a revised rat sequence was compared to that of the human aromatase PII promoter by BEST-FIT analysis, a region of about 300 bp was identified that was 80% conserved between the two promoters. A potential SF-1 site, CCAAGGTCA, was identified at position -82 within this region. An oligonucleotide probe containing this putative SF-1 site was used in gel mobility shift assays. Consistent with previous studies, a specific complex was observed with nuclear extracts from gonadal steroidogenic tissues but was absent with nuclear extracts from nonsteroidogenic tissues. The role of SF-1 in this steroidogenic cell-specific complex was next addressed more directly. Bacterial extracts containing an SF-1-glutathione S-transferase fusion protein interacted specifically with the putative SF-1 site, and polyclonal antisera against SF-1-glutathione S-transferase specifically abolished the complex formed with nuclear extracts from rat ovaries or R2C rat Leydig tumor cells. Finally, the aromatase SF-1 element increased expression of an SV40 promoter/luciferase construct in transient transfection experiments in a steroidogenic cell-selective manner. Collectively, these studies implicate SF-1 in the regulation of steroid hydroxylase gene expression in nonadrenal tissues, significantly extending previous studies in adrenocortical cells.
 ...
PMID:Steroidogenic factor 1, an orphan nuclear receptor, regulates the expression of the rat aromatase gene in gonadal tissues. 839 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>