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 cDNA encoding QPc-9.5 kDa (subunit VII) of bovine heart mitochondrial ubiquinol-cytochrome c reductase was cloned and sequenced. This cDNA is 665 base pairs long with an open reading frame of 246 base pairs that encodes an 81-amino acid mature QPc-9.5 kDa. The insert contains 395 base pairs of a 3'-noncoding sequence with a poly(A) tail. The amino acid sequence of QPc-9.5 kDa deduced from this nucleotide sequence is the same as that obtained by protein sequencing except that residue 61 is tryptophan instead of cysteine. The QPc-9.5 kDa was overexpressed in Escherichia coli JM109 cells as a glutathione S-transferase fusion protein (GST-QPc) using the expression vector, pGEX/QPc. The yield of soluble active recombinant GST-QPc fusion protein depends on the induction growth time, temperature, and medium. Maximum yield of recombinant fusion protein was obtained from cells harvested 3 h postinduction of growth at 27 degrees C on LB medium containing betaine and sorbitol. QPc-9.5 kDa was released from the fusion protein by proteolytic cleavage with thrombin. Isolated recombinant QPc-9.5 kDa showed one protein band in SDS-polyacrylamide gel electrophroesis corresponding to subunit VII of mitochondrial ubiquinol-cytochrome c reductase. Although the isolated recombinant QPc-9.5 kDa is soluble in aqueous solution, it is in a highly aggregated form, with an apparent molecular mass of over 1 million. Addition of detergent deaggreates the isolated protein to the monomeric state, suggesting that the recombinant protein exists as a hydrophobic aggregation in aqueous solution. The recombinant QPc-9.5 kDa binds ubiquinone and shows a spectral blue shift. Upon titration of the recombinant protein with ubiquinone, a saturation behavior is observed, suggesting that the binding is specific and that the recombinant protein may be in the functionally active state.
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PMID:Cloning, gene sequencing, and expression of the small molecular mass ubiquinone-binding protein of mitochondrial ubiquinol-cytochrome c reductase. 759 38

The effects on drug metabolizing enzymes of cyclopropenoid fatty acids present in baobab seed oil were evaluated in rats fed either a diet with baobab seed oil (1.27% cyclopropenoid fatty acids in the diet) or a diet with heated baobab seed oil (0.046% cyclopropenoid fatty acids in the diet). Comparison was made with rats fed a mixture of oils that contained no cyclopropenoid fatty acid. Rats fed baobab oil showed retarded growth. In comparison with the other groups, the relative liver weights were markedly increased whereas cytochrome P-450 content and NADPH cytochrome c reductase and NADH cytochrome c reductase activities were decreased. In rats fed the heated baobab oil the relative liver weight was decreased and the cytochrome P-450 level and reductase activities were increased relative to levels in rats fed the unheated oil. Ethoxycoumarin deethylase, ethoxyresorufin deethylase and pentoxyresorufin depentylase activities, expressed on the basis of cytochrome P-450, were greater in the group fed unheated baobab seed oil. Cytosolic glutathione transferase activity was markedly decreased in rats fed fresh baobab seed oil and heating the oil, which reduced the content of cyclopropenoid fatty acids, led to a considerable increase of this activity. UDP-glucuronyl transferase activities were not modified by the type of oil included in the diet. It is possible that the mechanisms of action of cyclopropenoid fatty acids are related to alterations of membrane lipid composition or microsomal proteins.
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PMID:Modifications of hepatic drug metabolizing enzyme activities in rats fed baobab seed oil containing cyclopropenoid fatty acids. 775 21

1. The effects of feeding allyl sulphides to rat (2000 ppm of the diet for 15 days) were investigated on various microsomal hepatic drug-metabolizing enzymes by their immunochemical detection and catalytic activity. 2. Allyl sulphides provoked a temporary dietary restriction, which enhanced the microsomal level of P450 and the activities of NADH-cytochrome c reductase and p-hydroxybiphenyl UDP-glucuronyltransferase (UDPGT 2), and lowered the activities of p-nitrophenol hydroxylase (PNPH), N-nitrosodimethylamine demethylase (NDMAD), laurate omega-hydroxylase (LAH) and glutathione S-transferase (GST). Therefore, pair-fed animals were used as a more relevant control for the dietary effects of allyl sulphides. 3. Diallyl sulphide (DAS) as well as diallyl disulphide (DADS) produced an enhancement of the microsomal level of P4501A2, 2B1/2 and 3A1/2, and epoxide hydrolase (EH) proteins, with an increase in the enzymatic activities they catalyse: ethoxyresorufin O-deethylase (EROD), aryl hydrocarbon hydroxylase (AHH), methoxyresorufin O-demethylase (MROD), ethoxycoumarin O-deethylase (ECOD), pentoxyresorufin O-depentylase (PROD), benzoxyresorufin O-debenzylase (BROD) and EH. Although P4502E1 proteins were lowered on treatment, NDMAD activity was not modified, and PNPH activity was even enhanced by allyl sulphides. Only DAS treatment raised erythromycin N-demethylase (ERDM) activity. 4. Both DAS and DADS increased the activity of GST and p-nitrophenol UDP-glucuronyltransferase (UDPGT 1), whereas UDPGT 2 activity was enhanced only by DAS.
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PMID:Modification of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl sulphides. 801 91

The activities of several phase I and phase II xenobiotic-metabolizing enzymes have been measured in liver microsomes and cytosol of male rats that had been fed for 15 days with diets containing beta-carotene or canthaxanthin (300 mg/kg diet) or an excess of vitamin A (70,000 IU/kg diet), or to which beta-carotene had been administered by ip injections (7 x 10 mg/kg body weight). Microsomal cytochrome P-450 and the associated NADH- and NADPH-cytochrome c reductases were assayed, as well as several phase I and phase II enzyme activities. Phase I activities were markers of the families 1, 2, 3 and 4 of P-450; phase II activities were microsomal UDP glucuronosyl transferases (UGT) and cytosolic glutathione S-transferase (GST). Canthaxanthin accumulated in liver to a much higher level than did ingested or injected beta-carotene. Canthaxanthin increased the liver content of cytochrome P-450 (control value x 1.7), and the activity of NADH-cytochrome c reductase (x 1.5), and of some P-450-dependent enzymes (ethoxy-, methoxy-, pentoxy- and benzoxyresorufin O-dealkylases; x98, x15, x6.5 and x13, respectively), but not of others (erythromycin N-demethylase, nitrosodimethylamine N-demethylase and laurate omega-hydroxylase). Phase II activities were also increased: UGT1 (x3.4), UGT2 (x1.2) and GST (x1.2). This induction profile, characterized by the very strong increase of the activity associated with P4501A1, and the co-induction of UGT1, closely resemble that of a classical inducer, 3-methylcholanthrene. By contrast, neither beta-carotene (fed or injected), nor an excess of vitamin A induced any significant variation of the enzyme activities measured.
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PMID:Effects of beta-carotene and canthaxanthin on liver xenobiotic-metabolizing enzymes in the rat. 807 Jul 38

Mitomycin C (MC), a clinically used natural antitumor agent, was shown to form three monoconjugates (11a-13a) and two bisconjugates (14a, 15a) with GSH upon reductive activation by rat liver microsomes, purified NADPH-cytochrome c reductase, or NADH-cytochrome c reductase or chemical reduction using H2/PtO2. Rat liver cytosol/NADH activated MC only at acidic pH (5.8), resulting in the formation of a single GSH-MC monoconjugate, 13a. The reductase responsible for cytosolic activation of MC to form this conjugate was DT-diaphorase. GSH itself did not reduce MC, and unreduced MC did not form conjugates with GSH. A moderate catalytic effect by glutathione S-transferase was demonstrated on the cytosol-activated reaction. Mercaptoethanol and N-acetylcysteine gave analogous sets of five MC-thiol conjugates under cytochrome c reductase or H2/PtO2 activation conditions. The structures of all 15 MC-thiol conjugates (five each with GSH, mercaptoethanol, and N-acetylcysteine, respectively) were determined, using 1H-NMR, UV, and mass spectroscopies, combined with analytical chemical and radiolabeling methods. The mechanism of formation of the conjugates features SN2 displacement of the carbamate of the reduced MC by GS-. The MC-GSH conjugates were noncytotoxic to the tumor cells tested. The conjugation of GSH with activated MC is likely to represent detoxication in mammalian cells. As another effect, GSH accelerates the rate of reduction of MC by "slow" reducing agents such as cytochrome c reductases and H2/PtO2. A mechanism is proposed to explain this effect, which involves further reduction of the initially formed MC semiquinone free radical by GSH.
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PMID:Conjugation of glutathione and other thiols with bioreductively activated mitomycin C. Effect of thiols on the reductive activation rate. 807 71

The dietary administration of beta-carotene (BC; 100 mg/kg food) daily has been found to be highly effective in reducing cancer incidence in male Sprague-Dawley rats fed 2-acetyl-aminofluorene (0.05% in food). BC treatment either before initiation, during initiation and selection/promotion phases of hepatocarcinogenesis have been found to be effective in elevating hepatic microsomal cytochrome b5 (24-50%), P-450 (18-38.5%), NADPH cytochrome c reductase (17.5-43.25%) and cytosolic aryl hydrocarbon hydroxylase (60.5-63.5%) activity to a statistically significant level measured either in the hyperplastic nodule (HN) or in the non nodular surrounding liver parenchyma (NNSP) compared to carcinogen control. Moreover, BC treatment throughout the study decrease the cytosolic 1-chloro-2,4-dinitrobenzene conjugated glutathione S-transferase (38.9-51.22%) and microsomal UDP-glucuronyl transferase (37.3-59.1%) activities to a significant level when compared to carcinogen control rats. A decrease in the number of hyperplastic nodules and their total liver parenchyma occupied were also observed in BC treated groups. Furthermore, a direct correlation between HNs and NNSP liver areas were observed with the hepatic BC and vitamin A contents and also with the rates and patterns of hepatic drug metabolism. Our results confirm the fact that BC is particularly protective in limiting the action of 2-AAF during the initiation phase of hepatocarcinogenesis.
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PMID:Inhibitory effect of beta-carotene on chronic 2-acetylaminofluorene induced hepatocarcinogenesis in rat: reflection in hepatic drug metabolism. 820 68

Female F344 rats received an i.p. injection of iron-dextran (600 mg Fe/kg) and then after 1 week were fed a diet containing 0.02% hexachlorobenzene (HCB) for up to 65 weeks. All rats (8/8) which received HCB after iron overload developed multiple hepatic nodules whereas only 3/8 rats administered HCB alone had nodules (average of one per positive liver). These hyperplastic regions were depleted of iron and were often positive for gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase P (GST-P). Telangiectasis and peliosis were prominent features in the lesions. Short-term experiments (5-15 weeks of iron/HCB treatments) showed that GGT and GST-P were induced early in the neoplastic process but not in discrete focal areas. Iron alone also caused some induction of these enzymes. Some cells with induced GST-P in either short or long term experiments also stained positively for this enzyme in the nucleus. Studies of cytochrome P450 mediated activities showed that at 5 and 15 weeks HCB had induced EROD (an estimate of CYP1A1), PROD (CYP2B1 activity) and BROD activities (CYP2B1 but also other isoenzymes). Under the influence of iron overload EROD was significantly depressed from HCB alone, but not the others or cytochrome P450 reductase. Cytosolic glutathione S-transferase activities were also induced by HCB, but, unlike microsomal EROD, preloading with iron enhanced the effects. In contrast, although cytosolic diaphorase activity was induced by HCB, this response was depressed in combination with iron. Glutathione peroxidase (with H2O2 as substrate) was depressed by both iron and HCB. Clearly, iron overload potentiates the neoplastic process induced by HCB in rats, with both enhancing and depressing effects on various enzyme activities induced by this chemical.
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PMID:Enhancement by iron of hepatic neoplasia in rats caused by hexachlorobenzene. 833 Mar 54

Effects of acute or subchronic administration of human placental extract (HPE), a worldwide clinically used agent, on hepatic drug metabolizing enzyme activities were evaluated in rats. Hepatic microsomal cytochrome P-450 (Cyt. P450) and cytochrome b5 (Cyt. b5) contents and cytosolic glutathione S-transferase (GST) activities were maximally induced after various periods of time following a single intraperitoneal injection of HPE (4 ml/kg) whereas microsomal UDP-glucuronyltransferase (UDPGT) activities were inhibited significantly. All these altered effects were returned almost to the basal levels after 96 h of treatment. Subchronic treatment (30 days) with HPE (1,2 or 4 ml/kg) afforded a significant induction of Cyt. P-450 and Cyt. b5 levels and that of GST activities with a concurrent suppression of the activities of UDPGT and these results were found to be dose-dependent. However, microsomal NADPH cytochrome c reductase activity was not affected either by acute or subchronic treatment. The observed variations in the levels and activities of above house-keeping enzymes were discussed in relation to the possible carcinogenic risk of long-term treatment with this pharmaceutical agent.
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PMID:Effects of human placental extract on hepatic drug metabolizing enzyme. 854 51

This study attempts to determine whether selenomethionine treatment can improve the survival time of mice inoculated with Dalton's lymphoma (DL) and thereby to identify phase/phases of the neoplastic processes at which selenium exerts its maximal action as an anticancer agent. Accordingly, a maximum of 30.76 and 143% increase in survival was brought about by treatment of selenomethionine prior to lymphoma transplantation, in comparison to mice receiving selenomethione supplementation concurrently with inoculation of DL, and those tumor-bearing mice receiving no supplementation, respectively. Beneficiality of selenomethionine has also been studied by monitoring the continuous changes brought about by this compound on hepatic total cytochrome P-450 and b5 content, NADPH cytochrome c reductase, UDP glucuronyl transferase and glutathione S-transferase (GST) activities. These are important biotransformation enzymes and are altered significantly in neoplasia. The drastic increase in all the markers studied, excepting GST, was effectively counteracted by selenomethionine treatment (more before than concurrently), which sufficiently delayed and controlled the increase in those xenobiotic indices. The 112 and 78.78% induction in GST activity brought about by prior and concurrent treatment of selenomethionine, respectively, confirms the fact that inducers of GSTs are often antitumorigenic.
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PMID:Selenomethionine in the inhibition of a transplantable murine lymphoma: reflection on hepatic drug metabolizing enzymes. 865 12

Crude oil pollution at drilling sites located within or in close proximity to agricultural pasture lands poses serious health risks to cattle raised on these lands. To investigate the clinical and systemic biochemical effects, cattle (8/group) were administered single oral doses of Pembina Cardium crude oil (PCCO) at 16.7, 33.4, and 67.4 g/kg, or water (control group) at 80 g/kg. Cattle exposed to PCCO showed dose-dependent clinical effects. At the lowest dosage, PCCO caused transient and minimal clinical effects; however, high dosages caused varied clinical signs which included tremors, nystagmus, vomiting, and pulmonary distress. On posttreatment day 7 or 30, four cattle from each treatment group were sacrificed and biochemical parameters were assayed in liver, lungs, and kidney cortex. In cattle monitored on posttreatment day 7, the PCCO-treated groups showed marked alterations from the control group in hepatic cytochrome P-450 (P-450), and in aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECOD) activities of these tissues. Administration of PCCO caused significant increases (> 100%) in hepatic P-450, but produced variable effects on AHH and ECOD activities in each tissue. The activity of AHH was increased in all tissues; however, the effect was highest in kidney cortex (> 5000%), followed by liver (> 500%) and lungs (> 250%). The activity of ECOD was altered in a differential manner. It was either increased markedly (>1300%) in kidney cortex or increased slightly (20-30%) in liver, but decreased (> 80%) in lungs. The activities of respiratory chain enzymes (succinate-cytochrome c reductase, NADH-cytochrome c reductase and cytochrome oxidase), or NADPH-cytochrome c reductase and glutathione transferase were not changed significantly in any tissues. The alterations in P-450, AHH, and ECOD observed on day 7 were markedly reversed in cattle examined on day 30 posttreatment, indicating a recovery from induced changes. Studies in vitro with hepatic microsomal preparations from day 7 posttreatment groups showed that increases in AHH and ECOD activity in PCCO-treated cattle were due to induction of new isoforms of P-450, as evidenced by (1) the appearance of a 448-nm spectral peak, and (2) differential inhibitory effects of metyrapone and 7,8-benzoflavone on AHH and ECOD activities.
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PMID:Biochemical effects of Pembina Cardium crude oil exposure in cattle. 885 67


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