S-(N-methylcarbamoyl)glutathione, a chemically-reactive glutathione conjugate, has been isolated from the bile of rats administered methyl isocyanate ... . The ability of this glutathione adduct to donate an N-methylcarbamoyl moiety to the free sulfhydryl group of cysteine was evaluated in vitro... . The glutathione adduct reacted readily with cysteine in buffered aqueous media (pH 7.4, 37 degrees C) and after 2 hr, 42.5% of the substrate existed in the form of S-(N-methylcarbamoyl)cysteine. The reverse reaction, ie between the cysteine adduct and free glutathione, also took place readily under these conditions. It is concluded that conjugation of methyl isocyanate with glutathione in vivo affords a reactive S-linked product which displays the potential to carbamoylate nucleophilic amino acids.
S-(N-Methylcarbamoyl)-N-acetylcysteine, a chemically labile mercapturic acid conjugate, was identified ... in the urine of rats dosed ip with methyl isocyanate (45.2 umol). The corresponding cysteine conjugate, however, was not detected in urine. ... The fraction of the injected dose of methyl isocyanate which appeared in 24 hr urine as S-(N-Methylcarbamoyl)-N-acetylcysteine ... was 24.8 +/- 1.9% (mean +/- SD, N=4). Thus, conjugation of methyl isocyanate with glutathione, followed by metabolism of the resulting S-(N-Methylcarbamoyl)-N-acetylcysteine adduct ... appears to represent a quantitatively important pathway of biotransformation of methyl isocyanate in the rat. However, in view of the known carbamoylating properties and in vitro cytotoxicity of S-linked conjugates of methyl isocyanate, it seems unlikely that the glutathione pathway of metabolism fulfills a conventional detoxification role in the case of methyl isocyanate. In contrast, it is proposed that carbamate thioester conjugates of methyl isocyanate, which can revert spontaneously to free methyl isocyanate under physiological conditions may actually contribute to the multisystem adverse effects of this highly toxic isocyanate in vivo.
... Methylisocyanate readily forms a glutathione conjugate in the lung after inhalation. From there, the conjugate is distributed to other tissues, where the reactive electrophilic parent cmpd may be regenerated. Such conjugates are considered transport forms of toxicants.
Monomethylamine, dimethylamine, and trimethylamine are endogenous substances as well as metabolites of methyl isocyanate, the /cmpd/ involved in the 1984 accident at Bhopal, India.
Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
Exposure to high levels of cyanide for a short time harms the brain and heart and can even cause coma, seizures, apnea, cardiac arrest and death. Chronic inhalation of cyanide causes breathing difficulties, chest pain, vomiting, blood changes, headaches, and enlargement of the thyroid gland. Skin contact with cyanide salts can irritate and produce sores. (L96, L97)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
暴露途径
这种物质可以通过吸入、皮肤接触和摄入被身体吸收。
The substance can be absorbed into the body by inhalation, through the skin and by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
... Female Wistar rats were given (14)C labeled /methyl isocyanate/ by ip injection or inhalation exposure, and free and protein bound radioactivity was determined in blood, brain, liver, kidney and lung samples. ... Free and protein bound radioactivity were present in all tissues within 30 minutes of the injection of methyl isocyanate at doses of 15 and 30 mg/kg. The relative order of activity in the tissues for both forms of radioactivity from highest to lowest was kidneys, liver, lung, brain, blood hemolysate. Brain radioactivity remained constant over a 10 day period during which the activity of the other tissues decreased. Radioactivity was present in the globin fractions of blood proteins and the hydantoin fractions of blood and tissue proteins. Methyl isocyanate exposure by inhalation produced comparable results.
The uptake and distribution of methyl isocyanate were studied in guinea pigs and mice. Male English guinea pigs ... were exposed to 0.5 to 15 ppm of (14)C labeled methyl isocyanate vapor for 1 to 6 hours. ... . Male and pregnant female Swiss Webster mice were exposed to 2.10 ppm of (14)C labeled methyl isocyanate for 6 hours. ... Methyl isocyanate derived (14)C activity was detected in venous and arterial blood within minutes of exposure; however, blood methyl isocyanate concentrations in animals exposed by way of the tracheal cannula were much lower than in those which breathed normally. Methyl isocyanate was cleared slowly from the blood; most of it was cleared within 3 days. Methyl isocyanate was cleared more rapidly from the urine than from bile. The highest concentrations of methyl isocyanate in male mice 2 hours after exposure were found in the lung, sternum, gastrointestinal tract, spleen, and kidney. Twenty four hours after exposure, highest methyl isocyanate concentrations were in the blood and lung. In female mice the highest concentrations at 2 hours after exposure were found in the lung, fetus, spleen, uterus, and kidney. After 24 hours the highest concentrations were in the lung, spleen, and fetus. /It was/ concluded that inhaled methyl isocyanate is taken up rapidly in the blood. This uptake is much higher in normal animals than in those breathing through a tracheal tube.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
这种物质可以通过吸入、皮肤接触和摄入被身体吸收。
The substance can be absorbed into the body by inhalation, through the skin and by ingestion.
Through the use of radioactively labeled methyl isocyanate (MIC), the deposition, penetration, and clearance of this highly reactive compound in the airway at the tissue and cellular levels have been directly examined. Guinea pigs were exposed to 14C-MIC vapors at concentrations ranging from 0.38 to 15.2 ppm for periods of 1-6 hr. Solubilization of tissues from these animals showed the airway tissues to have the highest level of radioactivity. In the nasal region, 14C deposition, as monitored by histoautoradiography, was limited to the epithelial layer, was related to dose, and was dependent on the specific epithelial cell type. The squamous epithelium was minimally labeled on the surface and the label did not penetrate the cell layer. However, radioactivity was detected throughout the entire nasal respiratory epithelial layer. The lack of nasal deposition in tracheotomized animals demonstrated that the 14C accumulation at this site was due to the scrubbing action of the nasal region with no contribution from blood recirculation. Cellular localization in the tracheobronchial region showed epithelial and subepithelial deposition in a dose-dependent manner with accumulation of the label at the subepithelial region. Radioactivity penetrated to the level of the terminal bronchiole but was not detected in the alveolar region. The persistence of airway radioactivity over the 48-hr postexposure period monitored suggests the covalent modification of airway macromolecules. Despite its broad specificity and high reactivity, MIC undergoes selective reactions in the airways which are dependent on respiratory region and cell type.
Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
申请人：Abbott Laboratories
公开号：US20040116518A1
公开（公告）日：2004-06-17
The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immune diseases and cerebral vasospasm, to pharmaceutical compositions containing these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
Geometrical isomerism in the S-alkyl thiohydroximate series: a new oxime fragmentation
作者：J. H. Davies、R. H. Davis、P. Kirby
DOI：10.1039/j39680000431
日期：——
S-alkyl thiohydroximates from the results of Beckmann rearrangements on both geometricalisomers. The anti-(alkylthio)-isomers undergo fragmentation under Beckmann conditions. The syn-(alkylthio)-isomers may be converted to the anti-isomers by irradiation with u.v. light. Other evidence concerning the geometry of this series of compounds is discussed.
Novel compounds of formula (I) Ar--(L--Ar').sub.q --(X).sub.k --(Y).sub.p --Q (I) wherein: k, p and q are independently 0 or 1; Ar represents either: (i) naphthyl, tetrahydronaphthyl, pyridyl or (ii) phenyl, optionally substituted, L is selected from --(CH.sub.2).sub.r -- (where r is 1-4), --O--, --CH.sub.2 O--, --CH.sub.2 S--, --OCH.sub.2 --, --CONH--, --NHCO--, --CO-- and --CH.sub.2 NH--, and, Ar' represents phenylene, thienylene or pyridylene optionally substituted, X represents oxygen, sulphur or carbonyl, Y is C.sub.1-10 alkylene or C.sub.1-10 alkenylene; Q represents a non-cyclic moiety selected from groups of formula ##STR1## in which one of m and n is 0 and the other is 1, R.sup.1 and R.sup.2 is selected from hydrogen, C.sub.1-4 alkyl, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.5-7 cycloalkylamino, C.sub.5-7 cycloalkyl (C.sub.1-4 alkyl) amino, anilino, N-C.sub.1-4 alkylanilino or Q represents a cyclic moiety selected from 1-hydroxy-1,3-dihydroimidazol-2-one and groups of formula ##STR2## in which Z represents a C.sub.2-5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom; and salts thereof.
Photodegradation of a 1,3,4-thiadiazole-urea herbicide. Isolation, characterization, X-ray crystal structure and synthesis of photoproducts
作者：Allan R. Moorman、David C. Findak、Han San Ku
DOI：10.1002/jhet.5570220360
日期：1985.5
The photodegradation of 1,3-dimethyl-1-(2-(3-fluorobenzylthio)-1,3,4-thiadiazol-5-yl)urea as a thin film and in solution is described. The two photoproducts from thin-film photolysis were characterized by spectral and synthetic methods. The X-raycrystalstructure of one of the photoproducts is also reported. The rearrangements were shown to involve an S-to-N benzyl migration, followed by a sulfur-oxygen
