Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The higher inhibition of liver microsomal carboxylesterase (CEase) by EPN, as compared to that of acetylcholinesterase (AchE) may be, at least in part, explained by the present findings that NAD potentiated the anti-CEase, but not anti-AchE, action of EPN. This phenomenon was referred to as "NAD-effect" in this paper. NAD-effect was not due to the increased formation of oxygen analog of EPN (EPN=O) by NAD addition through liver microsomal cytochrome P-450 catalyzed monoxygenase, because the amounts of EPN=O formed during incubation in the presence and absence of NAD were not significantly changed as shown by gaschromatography-mass spectrometric estimations. In addition, HAD-effect could be observed in the experiments even under carbon monoxide atmosphere. Such NAD-effect was observed only when NAD, EPN and an unidentified component bound to liver microsomal membrane were co-existent in the incubation mixture.
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PMID:Potentiation of ethyl para-nitrophenyl phenyl-phosphonothioate (EPN)-induced inhibition of liver microsomal carboxylesterase by NAD in vitro in rats. 23 May 54

The new cholinesterase reactivator alloxime, 10 mg/kg, shows a marked therapeutical benefits in acute intoxication rats with carbamine pesticides such as carbofuran, pirimor, elocron. The therapy of alloxime in combination with atropine, 10 mg/kg, results to their combined therapeutical effect, the toxicity of carbofuran, elocron, and pirimor (by LD50) decreasing by 8.4, 5.6, and 3.5 times, respectively). The mechanism of alloxime's therapeutical action is due to its capacity to restore cholinesterase activity in the central nervous system, normalizing neuromuscular transmission and hepatic and renal cytochrome P-450 levels.
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PMID:[The therapeutic efficacy of alloxime in experimental carbamate pesticide poisoning]. 130 79

The effects of repeated exposure to N,N-dimethylformamide (DMF) on hepatic microsomal monooxygenase system and glutathione metabolism were investigated. DMF was administered to Wistar male rats by subcutaneous (s.c.) injection at 0.5 ml/kg body weight daily for 1 week. Macroscopically, mild liver swelling was observed and liver weights significantly increased after 1 week of exposure to DMF. Hematological changes were not detected. In exposed rats, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, cholinesterase and total cholesterol significantly increased. Hepatic microsomal cytochrome P-450 and protoheme decreased by 34% and 24%, respectively, while microsomal protein and cytochrome b5 were not affected. NADH-ferricyanide reductase activity decreased by 24% while NADPH-cytochrome c reductase activity showed no change. Glutathione reductase (GR) activity showed a significant decrease after the first injection and remained depressed throughout the study, with no change in glutathione peroxidase (GPx) activity. Glutathione S-transferase (GST) activity showed a significant increase at 3 days after DMF treatment and gradually increased by 66% at 1 week. In a subsequent experiment with a single administration of DMF (4 ml/kg), reduced glutathione (GSH) in the liver was decreased by 28% at 8 h, but recovered to control levels by 24 h. These results indicate that DMF alters the hepatic microsomal monooxygenase system and glutathione metabolism. These findings may greatly contribute to the elucidation of the pathogenesis of DMF hepatotoxicity.
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PMID:Effects of dimethylformamide on hepatic microsomal monooxygenase system and glutathione metabolism in rats. 153 72

Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 degrees C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.
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PMID:Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion. 168 64

The joint neurotoxic action of simultaneous exposure to vapors of n-hexane and methyl iso-butyl ketone (MiBK) and dermally applied O-ethyl O-nitrophenyl phenylphosphonothioate (EPN) was studied in groups of five adult hens. Four groups of hens were concurrently exposed to a dermal 2.5 mg/kg of EPN, 1000 ppm of n-hexane and 100, 250, 500 or 1000 ppm of MiBK. Two groups were each exposed to binary mixtures of a dermal dose of 2.5 mg/kg of EPN and 250 ppm of MiBK or 1000 ppm of n-hexane. Another three groups of hens were exposed to either 250 ppm of MiBK, 1000 ppm of n-hexane or a dermal dose of 2.5 mg/kg of EPN. A Group of hens was kept untreated. All hens were terminated after 30 days of treatment. Hens exposed to MiBK or n-hexane vapor did not exhibit any toxicity signs. In contrast, hens treated with EPN alone or in combination with n-hexane and/or MiBK developed acute cholinergic and delayed neurotoxicity signs. Hen brain acetylcholinesterase and neurotoxic esterase activities were inhibited in hens treated concurrently with EPN, n-hexane and MiBK. MiBK alone or in combination with EPN and n-hexane induced liver microsomal cytochrome P-450 content and phenobarbital-inducible cytochrome P-450 enzyme activities. Microsomes from hens treated with EPN, n-hexane, MiBK or mixtures of EPN, n-hexane and MiBK significantly enhanced the biotransformation of EPN to the more neurotoxic oxidation metabolite O-ethyl O-4-nitrophenyl phenylphosphonate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of joint neurotoxicity of n-hexane, methyl isobutyl ketone and O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens. 201 92

Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20-21, 30 +/- 1 and 65 +/- 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.
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PMID:Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice. 226 58

In order to identify non-invasive, biochemical indicators of di(2-ethylhexyl)phthalate (DEHP) exposure, we have compared the effects in blood serum with biochemical effects in liver in rats fed a diet containing 0, 0.25, 0.75 and 2% DEHP for 2 weeks. After 3 days of treatment serum arylesterase activity levels and serum triglycerides were decreased to 60% and 20% of control values, respectively. After a 2-week treatment with DEHP the effects were generally stronger. Compared to a control group, serum arylesterase activity levels, serum triglycerides and serum cholesterol were decreased to 40%, 20% and 50%, respectively. Serum cholinesterase activity levels and serum albumin concentrations were increased by the DEHP treatment to 290% and 135% of control values, respectively. In the livers a hepatomegaly, an induction of cytochrome P-450 IVA1 and induction of the activity of palmitoyl-CoA oxidase and carnitine acetyl-CoA transferase was found to be 180%, 1080%, 1300% and 1700% of control values, respectively. The liver is a more sensitive target for DEHP exposure compared to the biochemical effects in serum, but determination of the serum parameters can be used to determine early biological effects of exposure to DEHP.
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PMID:Effect of di(2-ethylhexyl)phthalate on enzyme activity levels in liver and serum of rats. 227 65

The effect of the microsomal enzyme inducer beta-naphthoflavone (beta NF) on the development of organophosphorus-induced delayed neuropathy (OPIDN) was examined in two laboratories (VPI and MSU), utilizing two strains of White Leghorn hens. A single intraperitoneal injection of beta NF at 80 mg/kg body weight 48 h prior to administration of o-tolyl saligenin phosphate (TSP), the neuroactive metabolite of tri-o-tolyl phosphate (TOTP), caused a significant increase in hepatic microsomal cytochrome P-450 concentrations and aniline hydroxylase activities after 72 h in both strains. Hepatic carboxylesterase and cholinesterase activities were not affected by beta NF treatment in either strain. Administration of TSP in single subcutaneous doses of 20 and 25 mg/kg body weight (VPI) or 30 and 60 mg/kg body weight (MSU) caused significant inhibition of whole-brain neuropathy target esterase (NTE) activity 24 h postdosing, and hens subsequently developed clinical signs characteristics of OPIDN. beta NF had no significant effect on NTE inhibition or on initiation or severity of OPIDN clinical signs. However, OPIDN clinical signs were less severe in the strain of bird (MSU) with the higher intrinsic hepatic carboxylesterase activity and the higher beta NF-induced cytochrome P-450 concentration. The study indicates that microsomal enzyme induction, which has been shown to alleviate TOTP-induced delayed neuropathy, could not alleviate OPIDN resulting from exposure to TSP. This study also suggests that strain may affect susceptibility to TSP-induced delayed neuropathy.
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PMID:Effect of beta-naphthoflavone on o-tolyl saligenin phosphate-induced delayed neuropathy in two lines of chickens. 259 76

Pharmacokinetic studies of cocaine have been carried out only in the last decade, although its local anesthetic action and addictive properties have been known for almost 100 years. Elimination half-lives of cocaine in man estimated from serial plasma concentration are relatively short and range from 0.5 to 1.1 h after i.v. and 0.9-1.5 h after administration by the nasal or oral route. The bioavailability after nasal inhalation is about 60%. The bicyclic structure of cocaine is characterized by functional groups including N-methyl, carboxyl methyl ester, and benzoyl ester, which are susceptible to biotransformation. Hydrolysis of the benzoyl group to ecgonine methyl ester is catalyzed by plasma cholinesterase and is thus under monogenic control. The hydrolytic cleavage of the other ester group, methyl ester, to benzoyl ecgonine occurs spontaneously at body temperature. In contrast, N-demethylation of cocaine mediated by microsomal cytochrome P-450 produces norcocaine and this metabolite was shown to be pharmacologically active, the action being similar to cocaine.
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PMID:Cocaine: pharmacokinetics and biotransformation in man. 268 63

The present study is concerned with the involvement of strain differences in rodent sensitivity to organophosphorous compound-induced delayed neurotoxicity (OPIDN). The inhibitory effect of three doses of tri-o-cresyl phosphate (TOCP) on neurotoxic esterase (NTE) and acetylcholinesterase (AChE) in brain was compared in three strains of rat: Long-Evans (LE) animals, which have been reported to be sensitive to the neurotoxic effects of TOCP, and Sprague-Dawley (SD) or Fischer 344 (F344) strains, with which negative results have been obtained. Differences in basal levels were found for NTE (LE greater than F344) greater than SD, with a range of 4.87-7.47 nmol phenylvalerate hydrolyzed/mg protein), but not AChE. Strain differences in inhibition by TOCP were found with both assays, with Sprague-Dawley animals being much less sensitive to esterase inhibition than either Long-Evans or Fischer 344 rats. The ED50 values for NTE inhibition were estimated to be 458, 209, and 288 mg/kg for SD, F344, and LE rats, respectively. The ED50 values for AChE inhibition were estimated to be 1007, 408, and 420 mg/kg for SD, F344, and LE rats, respectively. Liver microsomes from the Fischer animals had less cytochrome P-450 than those from the other two strains. Differences in the ability of the strains to either form or inactivate the active metabolite of TOCP may account for the variation observed. While metabolism may play a role in the differences in the level of NTE inhibition in SD rats compared to the LE strain, it cannot account for the lack of sensitivity of the F344 animals to OPIDN. These results may be important in selecting a strain for the study of the toxic effects of organophosphorous compounds in rats.
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PMID:Variation between three strains of rat: inhibition of neurotoxic esterase and acetylcholinesterase by tri-o-cresyl phosphate. 318 97


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