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51.
52.
Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases 总被引:5,自引:0,他引:5
B I Ghanayem L T Burka H B Matthews 《The Journal of pharmacology and experimental therapeutics》1987,242(1):222-231
2-Butoxyethanol (BE) is a massively produced glycol ether of which more than 230 million pounds was produced in the United States in 1983. It is extensively used in aerosols and cleaning agents intended for household use. This creates a high potential for human exposure during its manufacturing and use. A single exposure of rats to BE causes severe hemolytic anemia accompanied by secondary hemoglobinuria as well as liver and kidney damage. Butoxyacetic acid (BAA) was earlier identified as a urinary metabolite of BE. In addition, we have recently identified two additional urinary metabolites of BE, namely, BE-glucuronide and BE-sulfate conjugates. The current studies were undertaken to investigate the metabolic basis of BE-induced hematotoxicity in male F344 rats. Treatment of rats with pyrazole (alcohol dehydrogenase inhibitor) protected rats against BE-induced hematotoxicity and inhibited BE metabolism to BAA. Pyrazole inhibition of BE metabolism to BAA was accompanied by increased BE metabolism to BE-glucuronide and BE-sulfate as determined by quantitative high-performance liquid chromatography analysis of BE metabolites in urine. There was approximately a 10-fold decrease in the ratio of BAA to BE-glucuronide + BE-sulfate in the urine of rats treated with pyrazole + BE compared to rats treated with BE alone. Pretreatment of rats with cyanamide (aldehyde dehydrogenase inhibitor) also significantly protected rats against BE-induced hematotoxicity and modified BE metabolism in a manner similar to that caused by pyrazole. Administration of equimolar doses of BE, the metabolic intermediate butoxyacetaldehyde, or the ultimate metabolite BAA caused similar hematotoxic effects. Cyanamide also protected rats against butoxyacetaldehyde-induced hematotoxicity. Further evidence of the involvement of metabolism in hematotoxicity was demonstrated by the administration of deuterium-labeled BE (1,1-dideuterio-2-BE) which resulted in a significant delay in the development of hematotoxicity. It is therefore concluded that: a) there is a strong correlation between the amount of BAA in the urine and BE-induced hematotoxicity; b) metabolic activation of BE via alcohol and aldehyde dehydrogenases is a prerequisite for the development of BE-induced hematotoxicity; and c) hematotoxicity induced by BE can be attributed to its metabolite BAA. Finally, the current studies may prove beneficial in the treatment of acute glycol ethers poisoning with alcohol dehydrogenase inhibitors. 相似文献
53.
Granulocyte-macrophage colony-stimulating factor mRNA stabilization enhances transgenic expression in normal cells and tissues 总被引:3,自引:1,他引:2
To increase transgenic production of granulocyte-macrophage colony- stimulating factor (GM-CSF), we mutated the mRNA's 3'-untranslated region, AUUUA instability elements. Expression vectors containing human or murine GM-CSF cDNAs coding for wild-type (GM-AUUUA) or mutant versions with reiterated AUGUA repeats (GM-AUGUA) were transfected into cells in culture or animals using particle-mediated gene-transfer technology. Normal peripheral blood mononuclear cells accumulated 20- fold greater levels of GM-CSF mRNA and secreted comparably greater amounts of cytokine after transfection with hGM-AUGUA expression vectors versus hGM-AUUUA. hGM-AUGUA mRNA was fivefold more stable (t 1/2 = 95 minutes) than hGM-AUUUA mRNA (t 1/2 = 20 minutes), accounting for elevated steady-state levels. Transfection site extracts and serum samples obtained 24 hours after gene transfer of hGM-AUGUA cDNA into mouse skin contained greater than 32 ng/mL and 650 pg/mL of GM-CSF protein, respectively, compared with 0.33 ng/mL and less than 8 pg/mL for hGM-AUUUA cDNA. GM-CSF produced from mGM-AUGUA cDNA transfected into rat abdominal epidermis induced a profound neutrophil infiltrate. These data suggest a novel strategy for enhanced production of biologically active cytokines by normal cells after in vivo gene transfer. 相似文献
54.
Musculoskeletal modelling in determining the effect of botulinum toxin on the hamstrings of patients with crouch gait 总被引:2,自引:0,他引:2
NS Thompson FRCS RJ Baker PhD AP Cosgrove MD FRCS IS Corry MD FRCS HK Graham MD FRCS FRACS 《Developmental medicine and child neurology》1998,40(9):622-625
This study aimed to determine the effect of hamstring botulinum toxin A (Btx-A) injection in 10 children with crouch gait in terms of changes in muscle length and lower-limb kinematics. Before Btx-A injection limb kinematics were recorded. Maximum hamstring lengths and excursions were calculated by computer modelling of the lower limb. Data were compared with the averaged hamstring lengths of 10 control children. Hamstrings were denned as short if their length was shorter than the average maximum length minus one standard deviation. Gait analysis was repeated 2 weeks after isolated hamstring Btx-A injection. Pre- and postinjection kinematic data and muscle lengths were then compared. Four of 18 injected limbs in three subjects had short medial hamstring before injection, none of the subjects had short lateral hamstrings. Muscle excursion was significantly reduced in the short and adequate maximum muscle length groups. A significant increase in the semimembranosus and semitendinosus length in all of the injected limbs was noted. Only in the short muscle group was a significant increase in muscle excursion observed. Knee extension improved by 13° in the adequate muscle length group and by 15.6° in the short muscle length group. Pelvic tilt and hip flexion increased in both groups non-significantly. Average walking speed postinjection increased from 0.60 ms-1 to 0.71 ms-1 . Short hamstrings are over-diagnosed in crouch gait. Hamstring Btx-A injection in patients with crouch gait produces significant, repeatable muscle lengthening and improved ambulatory function. 相似文献
55.
Trichloroethylene (TCE)1 is an important environmental contaminant, a well established rodent carcinogen, and a "probable human carcinogen". Metabolism of TCE occurs primarily via cytochrome P450 (P450)-dependent oxidation. In vitro studies suggested that CYP2E1 is the principal high-affinity enzyme responsible for TCE metabolism. The objective of the present work is to more directly assess the role of CYP2E1 in the metabolism and disposition of 1,2-14C-TCE administered at 250 or 1000 mg/kg (gavage) using Cyp2e1-/-[knockout (KO)] versus wild-type (WT) mice. After dosing, animals were individually placed in glass metabolism cages that allowed the collection of expired air, urine, and feces. Exhalation of TCE-derived 14CO2 increased in a dose-dependent manner in mice of both genotypes and was significantly higher in WT versus KO mice. A significantly greater percentage of the dose was exhaled in KO versus WT mice as organic volatiles (mainly as TCE). Urinary excretion was the major route of TCE metabolism in WT mice, and the percentage of dose eliminated in urine was significantly higher at the 250 versus 1000 mg/kg dose. Furthermore, urinary excretion and CO2 exhalation significantly decreased in KO versus WT mice. Pretreatment with 1-aminobenzotriazole clearly inhibited TCE metabolism as evident from increased exhalation of parent TCE, and decreased urinary excretion and CO2 exhalation in mice of both genotypes. In conclusion, these data showed that whereas CYP2E1 plays an important role in TCE metabolism and disposition, other P450s also play a significant role and may explain earlier results showing that TCE causes lung damage in KO and WT mice. 相似文献
56.
Berens RJ Meyer MT Mikhailov TA Colpaert KD Czarnecki ML Ghanayem NS Hoffman GM Soetenga DJ Nelson TJ Weisman SJ 《Anesthesia and analgesia》2006,102(4):1045-1050
Critically ill children are treated with opioid medication in an attempt to decrease stress and alleviate pain during prolonged pediatric intensive care. This treatment plan places children at risk for opioid dependency. Once dependent, children need to be weaned or risk development of a withdrawal syndrome on abrupt cessation of medication. We enrolled opioid-dependent children into a prospective, randomized trial of 5- versus 10-day opioid weaning using oral methadone. Children exposed to opioids for an average of 3 wk showed no difference in the number of agitation events requiring opioid rescue (3 consecutive neonatal abstinence scores >8 every 2 h) in either wean group. Most of the events requiring rescue occurred on day 5 and 6 of the wean in both treatment groups. Patients may be able to be weaned successfully in 5 days once converted to oral methadone, with a follow-up period after medication wean to observe for a delayed withdrawal syndrome. 相似文献
57.
Acetylcarbocholine and acetylsilicocholine: Directly or indirectly acting cholinergic spasmogens? 总被引:1,自引:0,他引:1
P. TH. HENDERSON E. J. ARIËNS B. W. J. ELLENBROEK A. M. SIMONIS 《The Journal of pharmacy and pharmacology》1968,20(1):26-35
The cholinergic and anticholinergic actions of nitrogen-free isosteres of acetylcholine and benzilylcholine are described. Esters of two kinds of choline analogues, carbocholine and silicocholine, were used. The spasmogenic activity of acetylcarbocholine and acetylsilicocholine on the guinea-pig ileum was identified as an indirect cholinergic action, in contrast to the direct cholinergic action of furtrethonium and the mainly non-cholinergic action of barium ions. In addition to this indirect cholinergic action, both esters show a weak anticholinergic and a weak noncompetitive “papaverine-like” spasmolytic activity. The corresponding benzilyl esters, although without an onium group, are relatively potent anticholinergic compounds. 相似文献
58.
Comparison of the hematologic effects of 2-butoxyethanol using two types of hematology analyzers 总被引:3,自引:0,他引:3
B I Ghanayem S M Ward P C Blair H B Matthews 《Toxicology and applied pharmacology》1990,106(2):341-345
Earlier reports from this laboratory indicated that 2-butoxyethanol (BE) causes acute hemolytic anemia in rats as evidenced by a time- and dose-dependent decrease in the number of red blood cells, in hemoglobin concentrations, and in hematocrits (HCT). Subsequent studies showed that treatment with BE causes an early increase in HCT and mean cell volume (MCV). Since this effect went undetected in our early work and resulted in the publication of inaccurate information, present studies were designed to reinvestigate the hematologic effects of BE using the laser-based hematology analyzer which was used in the early studies and an impedance-based hematology analyzer, simultaneously. Packed cell volumes (PCV; spun HCT) were also performed on all blood samples. Male F344 rats were treated with 0, 125, 250, or 500 mg BE/kg (po) and blood was collected from the retro-orbital venous plexus at 1, 2, 4, 8, and 24 hr after dosing. Hematology profiles of BE-treated rats obtained from the impedance-based analyzer showed an early dose- and time-dependent increase in HCTs and MCVs. In contrast, analysis of the same blood samples using the laser-based analyzer showed a dose- and time-dependent decrease in HCTs with little or no change in MCVs. Changes observed in PCVs were consistent with results obtained from the impedance-based analyzer. Therefore, under the experimental conditions of this and previous studies, the laser-based analyzer was unable to detect early increases in HCTs and MCVs in rats treated with BE. Finally, these data explain the different principles utilized to measure cell size by both instruments as they relate to the hematologic effects of BE. Moreover, present data show that BE-induced hemolysis of erythrocytes is preceded by a quantitatively unique and massive swelling suggesting the erythrocyte membrane as the target. 相似文献
59.
Cytochromes P450 (CYPs) comprise a number of enzyme subfamilies responsible for the oxidative metabolism of a wide range of therapeutic agents, environmental toxicants, mutagens, and carcinogens. In particular, cytochrome P450 2E1 (CYP2E1) is implicated in the oxidative bioactivation of a variety of small hydrophobic chemicals including a number of epoxide-forming drugs and environmentally important toxicants including urethane, acrylamide, acrylonitrile, benzene, vinyl chloride, styrene, 1-bromopropane, trichloroethylene, dichloroethylene, acetaminophen, and butadiene. Until recently, chemical modulators (inducers and inhibitors) were used in order to characterize the enzymatic basis of xenobiotic metabolism and the relationships between CYP-mediated bioactivation and chemical-induced toxicity/carcinogenicity. With the advent of genetically engineered knockout mice, the ability to evaluate the roles of specific CYPs in the metabolism of xenobiotics has become more attainable. The main focus of the current review is to present studies that characterized the enzymatic, metabolic, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity of various xenobiotics using Cyp2e1-/- mice. Data presented in this review demonstrated that the most comprehensive studies using Cyp2e1-/- mice, encompassing the entire paradigm of metabolism to toxicity, genotoxicity, and carcinogenicity were possible when a substrate was primarily metabolized via CYP2E1 (e.g. urethane and acrylamide). In contrast, when multiple CYP enzymes were prevalent in the oxidation of a particular substrate (e.g.: trichloroethylene, methacrylonitrile, crotononitrile), investigating the relationships between oxidative metabolism and biological activity became more complicated and required the use of chemical modulators. In conclusion, the current review showed that Cyp2e1-/- mice are a valuable animal model for the investigation of the metabolic and molecular basis of toxicity, genotoxicity, and carcinogenicity of xenobiotics. 相似文献
60.
S Sinha S Gupta S Malhotra NS Krishna AV Meru V Babu V Bansal M Garg N Kumar A Chugh A Ray 《British journal of pharmacology》2010,160(5):1119-1127