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 effects of a subclinical fascioliasis at various stages of its development (at week 3, 6 and 9 after infection by oral administration of 20 metacercariae of Fasciola hepatica) in rats were determined on the activity of enzymes involved in liver metabolism of glutathione and on the subunit pattern of cytosolic glutathione S-transferase. The parasitic pathology was ascertained by clinical observation of the rats and at autopsy. Hepatic microsomal cytochrome P-450 content was significantly decreased in infected rats by week 3 and 6 post-infection. Not correlatively, the catalytic activities of glutathione S-transferase towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were significantly lowered in last stages of the experimental fascioliasis (by week 6 and 9 post-infection). These decreases were correlated to that of subunit 1 as determined by means of high-performance liquid chromatography of cytosolic proteins whereas subunit 6 could also be decreased. Fascioliasis did not alter cytosolic glutathione, glutathione reductase and glutathione peroxidase activities or plasma glutathione S-transferase activity accepting 1-chloro-2,4-dinitrobenzene as the substrate.
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PMID:Differential inhibition of rat hepatic glutathione S-transferase isoenzymes in the course of fascioliasis. 205 25

The induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66, and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes.
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PMID:Mechanisms of anti-carcinogenesis by indole-3-carbinol. Studies of enzyme induction, electrophile-scavenging, and inhibition of aflatoxin B1 activation. 210 94

The metabolic capacity of reconstituted epidermis from the outer root sheath cells of human hair follicles was determined. It was found that this epidermis possesses enzymes involved in both phase I (oxidation) and phase II (conjugation) reactions for drug biotransformation. The use of model substrates allowed the characterization of several isoenzymes. The homogenate fraction contained membrane-bound mixed-function oxydases (cytochrome P-450 dependent) involved in the O-dealkylation of 7-ethoxy-, 7-pentoxy-, and 7-benzoxyresorufin, NADPH cytochrome c (P-450) reductase, testosterone 5 alpha-reductase, and UDP-glucuronosyltransferases, which conjugate 1-naphthol and bilirubin. One isoform of each glutathione S-transferase, steroid-, and arylsulfatases, acting on estrone- and 4-methylumbelliferone sulfates, was detected. Additionally, the activity of two distinct forms of epoxide hydrolases, which hydrate cis- and trans-stilbene oxides, could be measured. The presence of these drug metabolizing enzymes in the reconstituted epidermis indicates that it has a potential to serve as a model to study epidermal drug metabolism in vitro.
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PMID:Reconstituted epidermis: a novel model for the study of drug metabolism in human epidermis. 211 70

Capsaicin (CAP; 50 mg/kg body wt., p.o.) and/or ethanol (EtOH; 10% (v/v) in the drinking water) were given for a period of 30 days to male rats, and changes in hepatic drug-metabolizing enzymes were investigated. The EtOH alone tended to increase the microsomal parameters such as cytochrome P-450 content and enzyme activities of aniline hydroxylase, aminopyrine demethylase and UDP-glucuronyl transferase, while it did not affect the cytosolic enzyme activities of sulfotransferase and glutathione S-transferase. The administration of CAP without EtOH tended to decrease all of the parameters studied. In contrast, the ingestion of CAP with EtOH tended to increase even the elevated microsomal enzyme activities by EtOH alone. These data suggest that chronic alcohol ingestion could modify the potential for detoxification of xenobiotics in persons who regularly consume a large amount of hot peppers.
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PMID:Effects of capsaicin and ethanol on hepatic drug-metabolizing enzymes in rat. 211 94

The effects of pretreatment with symmetrically dihalogenated biphenyls (DXBs, X-F, Cl(C), Br(B) and I) on rat liver drug metabolism enzymes were investigated. 4,4'-DFB, -DCB, and -DBB as well as 2,2'-DFB appeared to be inducers of microsomal cytochrome P-450-linked monoxygenases (N-demethylases of aminopyrine and ethylmorphine). However, no structure-induction relationship was found. 4,4'-DXBs also induced a cytochrome P-448-linked mono-oxygenase (ethoxyresorufin O-deethylase), and their order of induction potential seemed to parallel the increase of the size of the halogen substituent. Therefore, 4,4'-DXB's may be categorized as mixed-type inducers, the cytochrome P-450 component being the more pronounced. Data on the cytochrome P-448 induction by dihalogenated biphenyls with only para substituents may be considered as a refinement of the previously described structure-activity relationship in this respect. All of the DXBs except 3,3'-DCB and 4,4'-DIB, enhanced, like phenobarbital, the activity of UDP-glucuronyltransferase toward 4-hydroxybiphenyl. Only 4,4'-DFB was able to induce the activity of glutathione S-transferase toward 1,2-epoxy-3-(p-nitrophenoxy)propane. Studies after 4,4'-DBB-treatment revealed, like phenobarbital, a preferential induction of ethylmorphine N-demethylase on rough endoplasmic reticulum-derived microsomes, whereas UDP-glucuronyltransferase activity toward 4-hydroxybiphenyl was induced to a larger extent on smooth endoplasmic reticulum microsomes, suggesting a dissimilar enzyme induction in microsomal subfractions.
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PMID:Induction of drug metabolism enzymes by dihalogenated biphenyls. 211 36

A qualitative and quantitative assessment was made of the development of hepatic drug-metabolizing enzymes (DME) in dogs as part of a study of the ability of animal test species to metabolize drugs. The following DME variables were measured in this study: amount of cytochromes P-450 and b5; activity of the NADPH and NADH-dependent reductases associated with each of these cytochromes; activity of cytochrome P-450-mediated enzymes, including aniline and coumarin hydroxylases, aminopyrine N-demethylase, and 7-ethoxycoumarin O-deethylase; activity of a uridine diphosphoglucuronic acid glucuronyl transferase with 4-methylumbelliferone as substrate; and glutathione-S-transferase activities, with dinitrochlorobenzene and dichloronitrobenzene as substrates. Most enzyme components had achieved maximal amount or activity by the fifth to eighth week after birth; they tended to decrease after weaning, although the activity of dichloronitrobenzene-glutathione transferase in geriatric dogs (312 to 525 weeks old) was approximately twofold greater than that of 8-week-old pups. There were no gender-related differences in any of the enzyme amounts or activities determined. Individual variation was pronounced even in the homogeneous colony from which these dogs were obtained.
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PMID:Maturational development of drug-metabolizing enzymes in dogs. 212 81

The effect of prolonged exposure to buthionine sulfoximine (BSO) on rat hepatic Phase I and Phase II drug-metabolizing enzymes has been examined. Exposure to 30 mM BSO in drinking water for 7 days induced hepatic microsomal UDP-glucuronosyltransferase activity (detergent-activated) toward p-nitrophenol (250%), 1-naphthol (210%), morphine (130%) and testosterone (140%), but not estrone. Glucuronosyltransferase activities were also induced after exposure for as short as 3 and as long as 13 days. When rats were returned to unsupplemented drinking water for 1 day prior to sacrifice following 6 days on 30 mM BSO, comparable induction to that seen after 7 consecutive days on the BSO solution was observed despite liver glutathione concentration having rebounded to 127% of control. Daily ingestion of BSO was similar (1 mmol/rat/day) for all periods of 30 mM BSO-drinking water exposure, with a body weight-adjusted dose range of 3.2-6.3 mmol/kg/day. An analogous inductive response caused by drinking 30 mM BSO for 3 days was elicited for p-nitrophenol and morphine glucuronidation by 6 mmol/kg doses of BSO given as single daily intraperitoneal or intragastric injections for 3 days. Intraperitoneal, intragastric and all BSO-drinking water exposures also significantly induced (130-195%) cytosolic glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Significant increases in UDP-glucuronosyltransferase and glutathione S-transferase activities were also observed following 3 days of exposure to BSO in the drinking water at a concentration as low as 5 mM. Cytosolic p-nitrophenol sulfotransferase activity, with one minor exception, was not enhanced by any BSO treatment regimen. Alterations in transferase activities were not accompanied by any major changes in either overall cytochrome P-450 concentration or oxidative reactions selective for two isozymes. Thus, in addition to its well-documented glutathione-depleting property, BSO also selectively induces several Phase II drug-metabolizing enzymes, an effect to be considered in studies employing extended BSO treatment.
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PMID:Induction of rat UDP-glucuronosyltransferase and glutathione S-transferase activities by L-buthionine-S,R-sulfoximine without induction of cytochrome P-450. 212 59

The nicotinamide administration to rats (50 mg/kg, subcutaneously, over 5 days) increased the concentration of liver cytochrome b5, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase and urinary excretion of bound glucuronic acid by 26.7, 33.1, 33.3, 53.0 and 31.0%, respectively. The chloral hydrate-induced sleep time in mice was reduced by 65%. Under similar experimental conditions the administration of equimolar amounts of diethylamide of nicotinic acid (75 mg/kg) exerted a more pronounced enzyme-stimulating effect. The cytochrome P-450 concentration, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase as well as the sulphobromophthalein elimination from blood plasma and urinary excretion of bound glucuronic acid were increased by 37.0, 33.1, 54.6, 80.5, 24.5 and 49.0%, whereas the chloral hydrate-induced sleep time decreased by 75%. The nicotinamide and diethylamide of nicotinic acid stimulating effects on xenobiotic biotransformation in rat liver are assumed to be due to enhanced NADPH, glutathione and UDP-glucuronic acid biosynthesis as well as their antioxidant properties.
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PMID:[A comparative study of the effects of nicotinamide and diethylnicotinamid on hepatic monooxygenase, glucuronyl and glutathione conjugating systems]. 215 Jun 2

We have identified a region in the 5' flanking sequence of the glutathione S-transferase (RX:glutathione R-transferase, EC 2.5.1.18) Ya subunit gene that contains a unique xenobiotic-responsive element (XRE). The regulatory region spans nucleotides -722 to -682 of the 5' flanking sequence and is responsible for part of the basal level as well as inducible expression of the Ya subunit gene by planar aromatic compounds such as beta-naphthoflavone (beta-NF) and 3-methyl-cholanthrene. The DNA sequence of this region (beta-NF-responsive element) is distinct from the DNA sequence of the XRE found in the cytochrome P-450 IA1 gene. In addition to the region containing the beta-NF-responsive element, two other regulatory regions of the Ya subunit gene have been identified. One region spans nucleotides -867 to -857 and has a DNA sequence with identity to the hepatocyte nuclear factor 1 recognition motif found in several liver-specific genes. The second region spans nucleotides -908 to -899 and contains a DNA sequence with identity to the XRE found in the cytochrome P-450 IA1 gene. The XRE sequence also contributes to part of the responsiveness of the Ya subunit gene to planar aromatic compounds. Our data suggest that regulation of gene expression by planar aromatic compounds can be mediated by a DNA sequence that is distinct from the XRE sequence.
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PMID:Regulation of glutathione S-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds. 216 79

Most compounds considered to be foreign to the human body are rather hydrophobic and chemically inert. Because of their hydrophobicity, xenobiotics enter the body easily by diffusion through biological membranes, are difficult to excrete in unchanged form in the urine and bile and accumulate in hydrophobic compartments of the cell, including the phospholipid bilayer of membranes, where they can disturb normal cellular functions. In order to transform xenobiotics into products which are more readily excretable, enzymes of detoxication first activate these substances (primarily via the cytochrome P-450 monooxygenase system) to intermediates which are often highly electrophilic and reactive, such as epoxides, free radicals and carbonium ions. These intermediates are then partially inactivated and their solubility in water simultaneously increased through the addition of water (by epoxide hydrolases) or conjugation with glutathione (by glutathione transferases). Finally, an additional increase in water solubility can be achieved by conjugation with, for example, sulfate (via sulfotransferases) and/or glucuronic acid (via UDP-glucuronyltransferases). Unfortunately, reactive intermediates of xenobiotic metabolism which are not inactivated sufficiently rapidly can bind covalently to many nucleophilic groups in the cell, including those on DNA, RNA and protein. Most often, because of various cellular defense mechanisms, such binding causes no serious damage. However, in some cases toxic and/or genotoxic effects may be produced. As an alternative to experimentation with animals, we have examined xenobiotic metabolism in circulating mononuclear leukocytes from human beings. Certain enzymes of detoxication--including membrane-bound and cytosolic epoxide hydrolases and cytosolic glutathione transferases--can be easily measured and characterized in preparations from these cells. Autosomal dominant hereditary differences of at least several hundred-fold in the activity of glutathione transferase mu in circulating human lymphocytes were observed, differences which may be of value in predicting an individual's risk for toxic/genotoxic damage after exposure to certain xenobiotics.
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PMID:The metabolism of xenobiotics and its relationship to toxicity/genotoxicity: studies with human lymphocytes. 226 43


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