共查询到20条相似文献,搜索用时 15 毫秒
1.
KW Skordos GL Skiles JD Laycock DL Lanza GS Yost 《Canadian Metallurgical Quarterly》1998,11(7):741-749
The existence of a cytochrome P450-dependent 2,3-epoxide of the potent pneumotoxin 3-methylindole was indirectly confirmed using stable isotope techniques and mass spectrometry. Determination of hydride shift and incorporation of labeled oxygen in 3-methyloxindole and 3-hydroxy-3-methyloxindole, metabolites that may be in part dependent on the presence of the epoxide, were utilized as indicators of the epoxide's existence. One mechanism for the formation of 3-methyloxindole involves cytochrome P450-mediated epoxidation followed by ring opening requiring a hydride shift from C-2 to C-3. Through incubations of goat lung microsomes with [2-2H]-3-methylindole, the retention of 2H in 3-methyloxindole was found to be 81%, indicating a majority of the oxindole was produced by the mechanism described above. 3-Hydroxy-3-methylindolenine is an imine reactive intermediate that could be produced by ring opening of the 2,3-epoxide. The imine may be oxidized to 3-hydroxy-3-methyloxindole by the cytosolic enzyme aldehyde oxidase. Activities of this putative detoxification enzyme were determined in both hepatic and pulmonary tissues from goats, rats, mice, and rabbits, but the activities could not be correlated to the relative susceptibilities of the four species to 3-methylindole toxicity. The 18O incorporation into either 3-methyloxindole or 3-hydroxy-3-methyloxindole from both 18O2 and H218O was determined. The 18O incorporation into 3-methyloxindole from 18O2 was 91%, strongly implicating a mechanism requiring cytochrome P450-mediated oxygenation. Incorporation of 18O into 3-hydroxy-3-methyloxindole indicated that the alcohol oxygen originated from molecular oxygen, also implicating an epoxide precursor. These studies demonstrate the existence of two new reactive intermediates of 3-methylindole and describe the mechanisms of their formation and fate. 相似文献
2.
3.
R Blasco E Moore V Wray D Pieper K Timmis F Castillo 《Canadian Metallurgical Quarterly》1999,181(1):149-152
We experienced a case of small cell carcinoma of the stomach in which chemotherapy had been markedly effective. A 54-year-old man was admitted to our hospital complaining of hematemesis. Gastric endoscopy showed a type 2 tumor at the lesser curvature of the cardia of the remnant stomach. Total gastrectomy, splenectomy and D2 lymph node dissection were performed. Histopathologically, the tumor was diagnosed as a small cell carcinoma with findings of t 2 n 1 in stage II, and conclusive curability was A. A month after the operation, CT-scan revealed multiple liver and lung metastases, so the patient was treated by combined chemotherapy with cisplatin and etoposide called PVP for three courses every four weeks for small cell lung cancer, which resulted in remarkable reduction of metastases (96% in the liver and 81% in the lung). This result suggests that PVP chemotherapy is effective in the treatment of small cell carcinoma of the stomach as well as the lung. 相似文献
4.
Metabolic activation of the hepatocarcinogen furan yields metabolites that react covalently with proteins. cis-2-Butene-1,4-dial is a microsomal metabolite of furan. This reactive aldehyde is thought to be the toxic metabolite that is responsible for the carcinogenic activity of furan. In order to characterize the chemistry by which this unsaturated dialdehyde could alkylate proteins, the products formed upon reaction of cis-2-butene-1,4-dial with model nucleophiles in pH 7.4 buffer were investigated. N(alpha)-Acetyl-L-lysine (AcLys) reacts with cis-2-butene-1,4-dial to form N-substituted pyrrolin-2-one adducts. N-Acetyl-L-cysteine (AcCys) reacts rapidly with cis-2-butene-1,4-dial to form multiple uncharacterized products. The inclusion of AcLys in this reaction mixture yielded an N-substituted 3-(S-acetylcysteinyl)pyrrole adduct which links the two amino acid residues. Related compounds were isolated when cis-2-butene-1,4-dial and glutathione (GSH) were combined. In this case, cis-2-butene-1,4-dial cross-linked two molecules of GSH resulting in either cyclic or acyclic adducts depending on the relative GSH concentration. Incubation of furan with rat liver microsomes in the presence of [glycine-2-3H]GSH led to the formation of radioactive peaks that coeluted with synthetic standards for the bisgluthathione conjugates. These studies demonstrate that the reactive cis-2-butene-1,4-dial formed during the microsomal oxidation of furan reacts rapidly and completely with amino acid residues to form pyrrole and pyrrolin-2-one derivatives. Therefore, this metabolite is a likely candidate for the activated furan derivative that binds to proteins. The ease with which cis-2-butene-1,4-dial cross-links amino acids suggests that pyrrole-thiol cross-links may be involved in the toxicity observed following furan exposure. 相似文献
5.
Induction of pulmonary edema and emphysema in goats by intraruminal administration of 3-methylindole
An elementary school in Broward County, Florida, reported an outbreak of scabies in January and February 1975. Investigation identified 23 cases of scabies in schoolchildren, with at least two cases in each grade. The first case had appeared as early as July 1974, but most occurred after December. There was little contact between students in different grades; most transmission was found to have taken place within families and in the community. An additional 28 cases were found in families and contacts; altogether, 51 cases in 24 families were identified on clinical or historical grounds. Infestation was more frequent in children who exchanged clothes with friends or relatives and in those who, on occasion, spent the night with other children. 相似文献
6.
Chlorothioketene has been suggested as a reactive intermediate formed by the cysteine conjugate beta-lyase-mediated cleavage of S-(1,2-dichlorovinyl)-L-cysteine, a minor metabolite of trichloroethene. Halothioketenes are highly reactive, and their intermediate formation may be confirmed by reactions such as cycloadditions and thioacylations of nucleophiles. A precursor of chlorothioketene, S-(1,2-dichlorovinyl)thioacetate, is readly accessible by the reaction of dichloroethyne with thioacetic acid. In presence of base, S-(1,2-dichlorovinyl)thioacetate is cleaved to chlorothioketene. Chlorothioketene is not stable at room temperature and was characterized after transformation to stable products by reaction with compounds such as cyclopentadiene, N,N-diethylamine, and ethanol. In organic solvents, the cleavage of S-(1, 2-dichlorovinyl)thioacetate in the presence of cytosine results in N4-acetylcytosine, N4-(chlorothioacetyl)cytosine, and small amounts of 3-(N4-thioacetyl)cytosine. No reaction products were seen with guanosine, adenosine, and thymidine under identical conditions. When cytosine was reacted with S-(1,2-dichlorovinyl)thioacetate in aqueous solutions, only N4-acetylcytosine was formed. N4-(Chlorothioacetyl)cytosine and 3-(N4-thioacetyl)cytosine were not detected even when using a very sensitive method, derivatization with pentafluorobenzyl bromide and electron capture mass spectrometry with a detection limit of 50 fmol/microliter of injection volume. Aqueous solutions of DNA cleave S-(1, 2-dichlorovinyl)thioacetate to give N4-acetyldeoxycytidine in DNA, but chlorothioketene adducts of deoxynucleosides were also not detected in these experiments. These results confirm the electrophilic reactivity of chlorothioketene toward nucleophilic groups of DNA constituents in inert solvents but also demonstrate that the formation of DNA adducts under physiological conditions likely is not efficient. Therefore, DNA adducts may not represent useful biomarkers of exposure and biochemical effects for trichloroethene. 相似文献
7.
In cancer chemoprevention trials, biomarkers as intermediate end points have gained importance. A variety of biomarkers have been proposed as intermediate end points for upper aerodigestive tract cancers. This study was aimed at studying the frequency of micronucleated cells and carcinogen DNA adducts as indicators of DNA damage and intervention end points in chemoprevention trials. Reverse smokers of chutta (rolled tobacco) from four villages numbering 298 in total were selected. Out of these, 150 were supplemented with four nutrients (vitamin A, riboflavin, zinc and selenium) and 148 controls received placebo, one capsule twice a week for 1 year. Slides of buccal smears were prepared and stained with Fuelgen reaction and counterstained with Fast Green and examined microscopically for the presence of micronucleated cells. Oral cell washings were collected and centrifuged. The DNA adducts were evaluated by the 32P post-labelling assay method. Protein and RNA free DNA (adducted) isolated from the cells was digested with MN/SPD and the DNA adducts isolated by the butanol enrichment procedure. The DNA adducts were identified and quantitated by multidimensional chromatography on PEI-TLC sheets by screen enhanced autoradiography and presented as RAL (relative adduct labelling) values. Both the micronuclei and DNA adducts were significantly elevated in subjects with lesions. At the end of 1 year the frequency of micronuclei decreased significantly (P < 0.001) in the supplemented subjects with or without lesions. The DNA adducts in the supplement group at the end of 1 year also reduced significantly. The adducts decreased by 95% in subjects with all categories of lesions and by 72% in subjects without lesions. No such effects were noted in the placebo group. The two biomarkers investigated in the case study appear to be modifiable by the administration of micronutrient supplements.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
8.
In rats, administration of 96% ethanol to the stomach causes ulcerative damages to its mucosa just 8 minutes later, which are of significant dimensions, reaching their maximum size following 3 hours. The sydnonimine psychostimulant OF-743 in combination with ethanol substantially reduces mucosal damage. The use of ethanol after OF-743 injections results in less ulcerative damage. The findings suggest that the drug has not only protective (preventive) effects, but beneficial properties. 相似文献
9.
DB Veprintsev SE Permyakov EA Permyakov VV Rogov KM Cawthern LJ Berliner 《Canadian Metallurgical Quarterly》1997,412(3):625-628
The thermal denaturation of bovine and human apo-alpha-lactalbumins at neutral pH has been studied by intrinsic protein fluorescence, circular dichroism (CD), and differential scanning microcalorimetry (DSC) methods. Apo-alpha-lactalbumin possesses a thermal transition with a midpoint about 25-30 degrees C under these conditions (pH 8.1, 10 mM borate, 1 mM EGTA), which is reflected in changes in both fluorescence emission maximum and quantum yield. However, the CD showed a decrease in ellipticity at 270 nm with a midpoint at about 10-15 degrees C, while DSC shows the transition within the region of 15-20 degrees C. The non-coincidence of transition monitored by different methods suggests the existence of an intermediate state in the course of the thermal denaturation process. This intermediate state is not the classical molten globule state which occurs at higher temperature (i.e. denatured state at these conditions) [D.A. Dolgikh, R.I. Gilmanshin, E.V. Brazhnikov, V.E. Bychkova, G.V. Semisotnov, S.Y. Venyaminov and O.B. Ptitsyn, FEBS Letters, 136 (1981) 311-315] and has physical properties intermediate between the native and molten globule states. 相似文献
10.
The purpose of the study was the direct detection of intact protein adducts-resulting from in-vitro incubations of flunoxaprofen- and benoxaprofen glucuronides in biological materials or originating from in vivo studies-by polyacrylamide gel electrophoresis (SDS-PAGE) followed by blotting and fluorescent scan, presumably yielding better specificity for the macromolecular binding partner and avoiding alkaline cleavage to release the aglycone. Glucuronides were isolated from urine samples or generated by incubation of aglycone with cofactors and rat liver microsomes. Following dialysis against BSA solution, SDS-PAGE and subsequent electrotransblotting were performed. Apparently, albumin represents the major binding protein for the covalent binding of these acyl glucuronides in plasma following incubation with blank plasma. In microsomal proteins two fluorescent peaks (appr. 39 and 62 KD) were identified for flunoxaprofen and benoxaprofen incubations. In vivo covalent binding was detected for both flunoxaprofen and benoxaprofen in plasma samples. For the racemically administered benoxaprofen a slight preponderance in adduct concentrations was found for the S-enantiomer. The pharmacokinetic analysis of in vivo data obtained for R/S-benoxaprofen (dose: 600 mg racemate) and S-flunoxaprofen (dose: 100 mg racemate), both of which have been withdrawn from the market, (employing a stereospecific HPLC method when analyzing volunteers' and patients' samples collected in the last 14 years, yet not stored longer than 3-4 years) demonstrated that significant amounts of glucuronides occur for both drugs (n = 2 for each compound; average Cmax values of the glucuronides: S-flunoxaprofen: 395 ng/ml; S-benoxaprofen: 775 ng/ml; R-benoxaprofen: 563 ng/ml). Presumably because of stereoinversion in humans, aglycone and glucuronide concentrations were higher for S- than for R-benoxaprofen. In vivo aglycone/glucuronide ratios were smaller for S- than for R-benoxaprofen, although in vitro incubation with human liver microsomes resulted in preferential glucuronidation of the R-enantiomer of benoxaprofen. Plasma concentration-time curves of the glucuronides paralleled those of the respective aglycones in their terminal phase. S-Benoxaprofen adduct concentrations were higher than R-benoxaprofen adduct concentrations (S: 28 ng/ml; R: 18 ng/ml covalently bound) and S-flunoxaprofen adduct concentrations with 29 ng/ml in the same range as S-beoxaprofen adducts, although for the latter the dose range as well as the respective glucuronide concentrations were higher. This indicates a higher reactivity of S-flunoxaprofen as opposed to S-benoxaprofen glucuronides. 相似文献
11.
12.
AM Jeffrey SH Blobstein IB Weinstein FA Beland RG Harvey H Kasai K Nakanishi 《Canadian Metallurgical Quarterly》1976,73(7):2311-2315
Arene oxides have been proposed as the reactive intermediates in the process of carcinogenesis induced by polycyclic aromatic hydrocarbons. The present study defines the structures of four guanosine adducts formed by the reaction of 7,12-dimethylbenz[a]anthracene-5,6-oxide with polyguanylic acid. The modified polymer was hydrolyzed to nucleotides and the hydrophobic guanosine adducts separated from unmodified guanosine by LH-20 column chromatograhy. The adducts were further resolved into four components (I-IV) by reverse phase high pressure liquid chromatography. Analysis of the ultraviolet, circular dichroism, mass, and proton magnetic resonance spectra of these compounds, or their acetate and free base derivatives, indicates that in all four compounds the aromatic hydrocarbon is present on the 2 amino group of guanine. Compounds I and IV, and II and III constitute diastereoisomeric pairs, respectively. In the I and IV pair, the adducts result from addition at the 6 position of the original dimethylbenz[a]anthracene oxide, whereas in the II and III pair, the addition occurs at the 5 position. Indirect evidence suggests that trans opening of the oxide occurred in all cases but this remains to be established. 相似文献
13.
S Waidyanatha K Yeowell-O'Connell SM Rappaport 《Canadian Metallurgical Quarterly》1998,115(2):117-139
A new method has been developed to detect mono-S-substituted cysteinyl adducts of 1,2- and 1,4-benzoquinone (BQ) in hemoglobin (Hb) and albumin (Alb). After reacting the protein with trifluoroacetic anhydride and methanesulfonic acid, the resulting isomers of O,O',S-tris-trifluoroacetyl-hydroquinone and -catechol are extracted and detected by gas-chromatography-mass spectrometry in the negative-ion chemical ionization mode. The limit of detection of the assay is about 20 pmol adduct/g protein. This assay was employed to quantitate mono-S-substituted background adducts in human and rat Hb and Alb and benzene-specific adducts in Hb and Alb from F344 rats following a single oral dosage of 50-400 mg [13C6]benzene/kg body wt. In Alb, a dose-related increase in both [13C6]1,2- and [13C6]1,4-BQ adducts was observed with [[13C6]]1,4-BQ-Alb] > [[13C6]1,2-BQ-Alb]. The formation of [13C6]1,2-BQ-Alb was linear with increasing dosage of benzene with a slope of 2.3 (pmol adduct/g protein)/(mg/kg body wt.) (S.E. = 0.18, R2 = 0.91). However, at dosages above about 100 mg [13C6]benzene/kg body wt., the levels of 1,4-BQ-Alb were greater than proportional to the dosage. Mono-S-substituted adducts of [13C6]1,2-BQ and [13C6]1,4-BQ were not detected in Hb. The background ([12C6]) adducts of 1,2- and 1,4-BQ in 20 F344 rats were estimated (in nmol adduct/g of protein) to be 3.9 (S.E. = 0.23) and 4.9 (S.E. = 0.30) in Hb and 2.7 (S.E. = 0.24) and 11.4 (S.E. = 0.60) in Alb. At the highest dosage of 400 mg [13C6]benzene/kg body wt., background levels of 1,2-BQ-Alb were about 4-fold higher than those of the benzene-specific adducts whereas the benzene-specific levels of 1,4-BQ-Alb were about 7-fold higher than those of the background adducts. Background levels of 1,2- and 1,4-BQ adducts in 10 portions of commercial human proteins were found to be (in nmol adduct/g of protein) 1.6 (S.E. = 0.05) and 0.85 (S.E. = 0.04) in Hb and 1.6 (S.E. = 0.06) and 8.9 (S.E. = 0.36) in Alb. 相似文献
14.
A new spin trap, 5-methyl-5-phenylpyrrolin-1-oxide (MPPO), has been evaluated with respect to the intrinsic stabilities of the hydroxyl and superoxide (or hydroperoxyl) radical spin adducts. Hydroxyl or superoxide radicals were generated using various sources in the presence of MPPO, and the hydroxyl or superoxide radical spin adduct of MPPO was detected by EPR spectroscopy. The time course of spontaneous decay of the EPR signal from hydroxyl or superoxide spin adducts followed first-order kinetics and the half-life was dependent on the pH of the medium. At pH 7.4 the half-life times are 76.4 and 5.7 min for the hydroxyl and hydroperoxyl/superoxide spin adducts, respectively. Structural factors which could influence the decay rates are also discussed. 相似文献
15.
Y Masubuchi S Igarashi T Suzuki T Horie S Narimatsu 《Canadian Metallurgical Quarterly》1996,279(2):724-731
Preincubation of microsomes from male Wistar rats with imipramine (IMI) in the presence of NADPH caused a time-dependent loss of bunitrolol 4-hydroxylase activity, indicating that the CYP2D enzyme is inactivated during IMI metabolism, which has also been observed after in vivo administration of IMI. A similar effect was obtained when desipramine, an N-demethylated metabolite of IMI, was used as an inhibitor, whereas 2-hydroxy-IMI had no effect on the activity. Thus, it seems likely that the inactivation of the CYP2D enzyme is related to 2-hydroxylation process of IMI. Incubation of microsomes with [3H]IMI in the presence of NADPH resulted in covalent binding of a 3H-labeled material to microsomal protein. Formation rates of the reactive metabolites covalently bound to protein followed Michaelis-Menten kinetics, and the K(m) value (1.1 microM) was close to that for microsomal IMI 2-hydroxylation. The metabolism-dependent covalent binding of [3H]IMI was lower in Dark Agouti rats, which is an animal model of CYP2D deficiency, than in Wistar rats. The binding was inhibited by propranolol and quinidine, a substrate and an inhibitor of CYP2D, respectively, and by an antibody against CYP2D. Similar strain difference (Dark Agouti < Wistar) and inhibitory effects by the compounds and the antibody were observed in IMI 2-hydroxylase but not in N-demethylase activity. SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) of microsomal protein incubated with [3H]IMI and NADPH showed that the binding was prominent at the molecular mass of approximately 50 kDa, which would be consistent with the P450 protein being a target for the binding. Furthermore, proteins to which [3H]IMI metabolites covalently bound were immunoprecipitated with the anti-CYP2D antibody. These results suggest that IMI is biotransformed into a chemically reactive metabolite (probably arene-oxide) through its 2-hydroxylation step by the CYP2D enzyme in rat liver microsomes, and the metabolite binds covalently to the enzyme itself, resulting in the inactivation. 相似文献
16.
J Braun S Laitko J Treharne U Eggens P Wu A Distler J Sieper 《Canadian Metallurgical Quarterly》1994,53(2):100-105
A recently developed technique, non-isotopic single strand conformation polymorphism analysis (PCR-SSCP), was applied to study the conserved feature of 4.5S RNA gene in enterobacteria. The 4.5S RNA gene was amplified by the polymerase chain reaction, using the template DNA extracted respectively from five strains of Escherichia coli and three strains of different genera in Enterobacteriaceae, i.e. Proteus vulgaris, Serratia marcescens and Enterobacter aerogenes. The PCR products were then carried out SSCP analysis. The experimental results showed that there seemed to be no detectable differences in the size and single strand conformation of 4.5S RNA genes from above strains, except the negative strand conformation of Enterobacter aerogenes. Thus it can be seen that the secondary structures of 4.5S RNA gene in enterobacteria are quite conservative. 相似文献
17.
18.
Pavel Janos Pavel Kuran Martin Kormunda Vaclav Stengl Tomas Matys Grygar Marek Dosek Martin Stastny Jakub Ederer Vera Pilarova Lubos Vrtoch 《中国稀土学报(英文版)》2014,32(4):360-370
Cerium dioxide was used for the first time as reactive sorbent for the degradation of the organophosphate pesticides parathion methyl,chlorpyrifos,dichlofenthion,fenchlorphos,and prothiofos,as well as of some chemical warfare agents—nerve gases soman and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate(VX).CeO2 specimens were prepared by calcination of basic cerous carbonate obtained by precipitation from an aqueous solution.The CeO2 samples containing certain amounts(1 wt.%–5 wt.%) of the neighboring lanthanides(La,Pr,Nd) were prepared in a similar way from pure lanthanide salts.It was shown that ceria accelerated markedly the decomposition of parathion methyl causing the cleavage of the P-O-aryl bond in the pesticide molecule.A similar reaction mechanism was proposed for the degradation of other organophosphate pesticides and nerve agents.The degradation times(reaction half-times) were in an order of minutes in the presence of CeO2,compared to hours or days under common environmental conditions.The reaction in suitable organic solvents allowed conversions of about 90% for parathion methyl loading of 20 mg pesticide/g CeO2 within 2 h with a reactant half-life in the order of 0.1 min.The key parameter governing the degradation efficiency of CeO2 was the temperature during calcination.At optimum calcination temperature(about 773.15 K),the produced ceria retained a sufficiently high surface area,and attained an optimum degree of crystallinity(related to a number of crystal defects,and thus potential reactive sites).The presence of other lanthanides somewhat decreased the reaction rate,but this effect was not detrimental and permitted the possible use of chemically impure ceria as a reactive sorbent.A fast organophosphate degradation was demonstrated not only in non-polar solvents(such as heptane),but also in polar aprotic solvents(acetonitrile,acetone) that are miscible with water.This opens new possibilities for designing more versatile decontamination strategies.The cleavage of phosphate ester bonds is of a great importance not only for the degradation of dangerous chemicals(chemical weapons,pesticides),but also for interactions of ceria(especially the nano-sized one) in biologically relevant systems. 相似文献
19.
《Acta Metallurgica Materialia》1991,39(8):1901-1913
In this study, constant stress creep tests were combined with detailed transmission electron microscopy in order to characterize and explain the intermediate temperature creep properties of Ni3Al. It was observed that octahedral glide, the mechanism associated with the anomalous yielding behavior of this alloy, is exhausted during primary creep. Primary creep does not lead to steady state creep but is instead followed by inverse creep. TEM observations indicate that the Kear-Wilsdorf locks that are formed during primary creep do lead to the exhaustion of octahedral glide, but that given sufficient time and temperature these cross-slipped segments are able to bow out and glide on the cube cross-slip plane. This dislocation generation, and subsequent glide, on the (010) plane is the basis for the observation of inverse creep in this alloy. Dislocation motion on the cube plane is a thermally activated process and as such is able to explain the strong temperature dependence that was observed for the intermediate temperature creep strength of Ni3Al. 相似文献
20.
武钢3号高炉中修开炉实践 总被引:1,自引:0,他引:1
1 概况 武钢3号高炉(1513m~3)第二代炉役于2001年6月15日停炉中修。2002年6月份,由于钢铁市场的变化,公司要求3号高炉于9月份中修投产。这次中修改造,只更换了第4~8段冷却壁、第4段冷却壁以上内衬及炉喉钢砖,对炉顶设备进行了整体更换,将原来 相似文献