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The glutathione conjugation of 2-chloro-, 3-chloro-, 4-chloro- and 2,6-dichlorobenzylidene malononitrile (chloroBMNs) was investigated in vitro. In incubation mixtures containing rat liver cytosol (9000 g), the decrease in the initial amount of glutathione due to the various chloroBMNs ranged from 40 to 60% and occurred both enzymatically and spontaneously at physiological conditions (37°C, pH7.4). 2,6-DichloroBMN, however, depleted glutathione largely spontaneously (38±3%). The steric hindrance of the two chlorosubstituents probably plays an important role during the glutathione-S-transferase catalyzed reaction.The hydrolysis of the chloroBMNs to the corresponding chlorobenzaldehydes and malononitrile was studied in a mixture of buffer pH 7.4 and ethanol. The rate of hydrolysis of 2,6-dichloroBMN was slower than those of the related chloroBMNs. This means that 2,6-dichloroBMN will be the most stable compound in the presence of water.Only IP administration of 2-chloroBMN (CS) to adult male Wistar rats gave enhancement of urinary thioether excretion. A thioether could be isolated and was identified as the N-acetyl-S-[2-chlorobenzyl]-L-cysteine. The quantity of this benzylmercapturic acid in the urine of rats amounted to 4.4% dose (0.07 mmol/kg, n=12).After IP administration of 2-chloro- and 3-chlorobenzaldehyde to rats benzylmercapturic acid excretion in the urine was found to be 7.6 and 1.1% of the dose, respectively. Administration of the related 4-chloro- and 2,6-dichlorobenzaldehyde, however, resulted in no urinary mercapturic acid excretion.It is very likely that in rats the initial biotransformation of chloroBMNs is mainly hydrolysis to corresponding chlorobenzaldehydes, leading in the case of 3-chloro-, 4-chloro- and 2,6-dichloroBMN to no mercapturic acid excretion in the urine.Nevertheless, 2,6-dichloroBMN will be the most reactive compound with proteins and therefore the best haptene in comparison with the related chloroBMNs.This work was financially supported by a grant from the Dutch Foundation for Medical Research FUNGO, grant no. 13-28-57 相似文献
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Frank Wiedemann Ralf Link Konrad Pumpe Ulrich Jacobshagen Hans E. Schaefer Karl-Heinz Wiesmüller Rolf-Peter Hummel Günther Jung Wolfgang Bessler Traudel Bltz 《The Journal of pathology》1991,164(3):265-271
The inflammatory reactions following subcutaneous application of adjuvants revealed characteristic pathological patterns. The injection of complete Freund's adjuvant (CFA) resulted in the formation of large lipid deposits encircled by an inflammatory reaction and concentrically arranged collagen bundles. Bacterial lipopolysaccharide (LPS) caused granulomatous aggregations of mononuclear cells with thrombotic vessel occlusions. Inoculation of the lipopeptide adjuvants induced accumulation of mononuclear cells with only minimal fibrotic changes which were resolved after day 28. Lipopeptide conjugates based on the head group tripalmitoyl-S-glyceryl-cysteinyl-serin (P3CS) can thus be used as effective immunogens and adjuvants without long-term tissue damage. 相似文献
5.
K T Kray E N Squire W R Tipton J C Selner J O'Dea H S Nelson 《The Journal of allergy and clinical immunology》1985,76(4):623-627
A formulation of 2% cromolyn sodium (CS) ophthalmic solution without the preservative, 2-phenylethanol, was compared with placebo in 58 patients with seasonal allergic conjunctivitis. Selection was based on history and positive skin tests. Neither immunotherapy nor use of antihistamines was allowed. This study was double-blinded and stratified by RAST scores to assure comparable groups. Either CS or placebo was used six times daily. Patients were observed weekly for 5 weeks during the peak of the fall weed-pollen exposure. Nasal symptoms were treated as required with beclomethasone nasal spray, and uncontrolled ocular symptoms were treated with boric acid and ephedrine solution. Nasal and ocular symptoms were recorded. There was a significant suppression of eye symptoms in the group receiving CS ophthalmic solution (p less than 0.02) during weeks 2, 4, and 5. There was a trend for nasal symptoms and the requirement for nasal beclomethasone to be less in patients receiving CS. 相似文献
6.
Charles W. Spurr William F. Prokasy William C. Williams Craig G. Clark 《Psychophysiology》1977,14(5):468-474
In an effort to determine whether or not conditioning is possible when CS intensity is at least as high as US intensity, nine groups of human subjects were employed in a skin conductance conditioning study. White noise CS and US intensities of 95- and 115-dB were varied orthogonally in the experimental groups, while control groups were incorporated to control for overall signal frequency and differences in habituation rates attributable to differences in intertrial interval. By conventional contrasts first interval response (FIR) conditioning was observed, but when controls for differential habituation rates were incorporated in the contrasts there was no evidence of FIR conditioning. Second interval response (SIR) conditioning was obtained, but it was manifest as an anticipatory response to the higher of two US intensities rather than in conventional conditioning vs control group comparisons. It was also shown that high CS intensities induce suppression of SIR levels, with greater suppression associated with the higher intensity. Several conclusions were made: 1) in a simple trace conditioning paradigm with skin conductance responding as the measure, it is not clear that what we have typically called a conditioning effect is separable from an habituation effect; 2) conditioning is possible even when CS intensity is as high as or higher than US intensity; and 3) the use of time sample measurement in the absence of signals provides a useful baseline for determining overall increases and decreases in SIR level. 相似文献
7.
Influence of environmental and genetic factors on variation in human response to DNA damaging agents
Green MH 《Environmental toxicology and pharmacology》1996,2(2-3):151-155
Exogenous DNA damaging agents must be considered in the context of endogenous reactive species which have the potential to damage DNA. Although a no-effect level for a DNA-damaging compound may not exist, it may be feasible to define a level where reducing exposure to the compound is no longer the most effective way of reducing human risk. Modifying environmental factors which affect human response to damage may be the better strategy. Although a number of rare human syndromes are associated with a reduced ability to repair DNA damage, it is not clear how wide is the range of genetic variation in repair capacity among normal individuals. Studies with DNA repair-deficient human syndromes indicate that processes other than mutation and DNA repair must be involved in the development of cancer, and these processes may represent new sources of variation in human response to genotoxic agents. 相似文献
8.
从云南美登木共生放线菌菌株(Streptomyces sp.)CS的发酵产物中分离得一个新的多羟基环己烷衍生物,并通过波谱学特征鉴定化合物的结构为1-isobutyroxymethyl cyclohex-1(6)-ene-2,3,4,5-tetrol-2-isobutyrate. 相似文献
9.
上海市区级医院剖宫产指征及影响因素分析 总被引:6,自引:0,他引:6
目的了解剖宫产指征及分析高剖宫产率的相关影响因素。方法对2001年5月~2003年2月到上海市3所区级妇幼保健院做产前检查的孕妇进行问卷调查。结果在933名基线调查对象中,剖宫产率为37.6%,居于前4位的剖宫产指征分别为胎儿宫内窘迫(36.5%)、社会因素(35.9%)、相对性头盆不称(18.5%)和妊娠合并症(6.3%)。回归分析发现,孕前体重超重、对分娩没有信心及胎儿体重在4000g以上的对象剖宫产的可能性大。结论目前上海市的剖宫产率相当高,胎儿宫内窘迫和社会因素已成为最主要的剖宫产指征,较高的剖宫产率与孕妇的心理因素和某些人口学特征(孕妇及胎儿体重)密切相关。 相似文献
10.
以组蛋白去乙酰化酶为靶标的抗癌药物研发进展 总被引:5,自引:0,他引:5
基因表达的精确控制是细胞增殖分化和器官正常生长和发育的基础。基因转录和激活程序依赖于组蛋白乙酰化酶(histone acetylase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)的协同作用。当HDAC过度表达并被转录因子募集,就会导致特定基因的不正常抑制,从而导致癌症及其他疾病。目前以HDAC作为抗癌靶点的研究方兴未艾,现综述HDAC类似蛋白(HDLP)的晶体结构和当前存在的HDAC抑制剂的作用机制、结构种类、研发状况和构效关系,以及新的HDAC抑制剂CS055的研发策略。 相似文献