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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, the question was raised as to why iso-OMPA, generally known as a selective irreversible inhibitor of butyrylcholinesterase (BuChE), potentiates soman toxicity in rats but not in mice. Mice are known to have higher carboxylesterase (CarbE) and lower BuChE activity in plasma than rat. It could be hypothesized that it is the iso-OMPA inhibition of plasma CarbE, and not of BuChE, which is responsible for potentiation of soman toxicity in iso-OMPA-pretreated rats. In order to test this hypothesis two doses of iso-OMPA were administered to rats prior to soman. The two doses were selected in such a way that both were high enough to inhibit more than 90% of plasma BuChE activity; plasma CarbE activity, however, was only slightly inhibited by the lower and substantially by the higher dose of iso-OMPA. Our results demonstrate that iso-OMPA-induced potentiation of soman toxicity correlates with the inhibition of CarbE and not with the inhibition of BuChE activity in rat plasma. Relative resistance of mice to iso-OMPA-induced potentiation of soman toxicity could therefore be explained by a higher proportion of CarbE activity remaining uninhibited after iso-OMPA pretreatment. By having their active centers unoccupied, CarbE molecules can bind soman and reduce its concentration in neuronal tissue and motor end-plates.
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PMID:Iso-OMPA-induced potentiation of soman toxicity in rat correlates with the inhibition of plasma carboxylesterases. 324 52

Cholinesterases were characterized in the serum of 77 treated and 11 untreated patients having primary carcinomas of various tissue origins and 21 healthy volunteers which served as controls. In most of the samples, pseudocholinesterase (BuChE) accounted for almost all cholinesterase (ChE) activity and was inhibited by the organophosphorous poison tetraisopropyl pyrophosphoramide (iso-OMPA). In samples from the tumor-bearing patients, ChE degraded 733 +/- 59 nmole acetylcholine/h/mg protein, lower than the 960 +/- 175 nmole/hour/mg levels measured in controls. Tumor serum ChE exhibited elevated sensitivity to 1,5-bis-(4-allyldimethyl ammonium phenyl)-pentan-3-one dibromide (BW), the selective bisquaternary inhibitor of "true" acetylcholinesterase (AChE), with no correlation to age, sex, staging of tumor, presence of metastases or the specific treatment protocol, and with a different distribution pattern from the decrease in ChE specific activity or the sensitivity to iso-OMPA. In sucrose gradients, ChE sedimented as 12S in controls whereas in tumor serum samples from treated patients an additional component of 6 to 7 S, inhibited by both iso-OMPA and BW, also was detected. However, the ChE activity in serum of patients with diagnosed carcinomas before surgery and medical treatment appeared to be nondistinguishable from controls. These findings suggest that the modified properties of serum cholinesterases in carcinoma patients are not the result of the tumor itself, but that the common therapy protocols used in the treatment of primary carcinomas may cause the appearance of soluble ChE activity with properties of both AChE and BuChE, which accumulates in the serum.
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PMID:Modified properties of serum cholinesterases in primary carcinomas. 333 35

Male Sprague-Dawley rats, injected with the irreversible acetylcholinesterase (AChE) inhibitor soman (pinacolyl methylphosphonofluoridate) 25 micrograms/kg sc, showed no signs of toxicity. Pretreatment with iso-OMPA (tetraisopropylpyrophosphoramide) 1 mg/kg sc 1 h before the soman administration, caused severe signs of hypercholinergic activity, similar to those seen with an acute signs-producing nonlethal dosage (100 micrograms soman/kg sc). Within 1 h iso-OMPA alone significantly reduced the activity of carboxylesterases (CarbE) in all tissues studied and butyrylcholinesterase (BuChE) activity was significantly reduced in plasma (22%) and liver (27%). Soman (25 micrograms/kg) alone significantly reduced the plasma activity of CarbE (15%), BuChE (53%) and AChE (18%), but had no effect on these enzymes of liver. The combined treatment of iso-OMPA and soman, however, reduced CarbE activity in liver (0%) and produced significantly greater effects than iso-OMPA or soman alone on AChE and BuChE in all the brain areas and skeletal muscles tested. The number of necrotic lesions found in skeletal muscles was many times higher with the combined treatment than seen with soman (25 micrograms/kg) alone, and was equal to those seen with an acute toxicity signs-producing dose of soman. It is concluded that the observed iso-OMPA-induced potentiation of soman toxicity is probably caused via reduced nonspecific binding sites (BuChE and CarbE) for soman leading to greater inhibition of AChE.
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PMID:iso-OMPA-induced potentiation of soman toxicity in rat. 343 75

Activity of acetylcholinesterase (EC 3.1.1.7) and pseudocholinesterase (EC 3.1.1.8) was measured in extracts from chick corneas, in a developmental series from days 7-20 of incubation and at three ages after hatching. Enzyme activity was measured by the biphasic single-vial radiometric assay of Johnson and Russell using [3H-acetyl]choline as substrate. Pseudocholinesterase was inhibited with tetraisopropylpyrophosphoramide (iso-OMPA). True acetylcholinesterase activity was verified by control assays run in the presence of both iso-OMPA and the true acetylcholinesterase inhibitor, 1:5-bis(4-allyldimethyl-ammonium phenyl)-pentane-3-one diiodide (BW284c51). With both inhibitors present, no cholinesterase activity was detected. Corneal acetylcholinesterase had an average Km of 1.1 +/- 0.3 X 10(-3) M at day 7, 14, and 20 of development and retained 90% activity even after 3 hr at 26 degrees C. At least 90% of the total cholinesterase activity was solubilized by Triton X-100 and sonication treatment. Activity decreased with increasing concentrations of NaCl present in the assay. A 60-fold transient increase in acetylcholinesterase specific activity occurs during the period from days 7-20 of embryonic development. This increase begins on the first day measured (day 7), progresses steadily and rapidly during the subsequent week, reaches a peak at day 15, and then decreases rapidly before hatching to a level maintained into adulthood. A similar pattern of transient appearance of highly sialylated gangliosides seen previously on days 14-17 leads to an hypothesis of a structural linkage between acetylcholinesterase and the plasma membrane lipids of corneal epithelial cells.
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PMID:Acetylcholinesterase activity in the cornea of the developing chick embryo. 357 Jun 95

A series of organophosphorous compounds (OP) was tested using a pharmacohistochemical method applied in vitro on the rat striatum, the central structure which contains the highest levels of acetylcholine and its metabolic enzymes; the OP showed a great variety of action towards the specific cholinesterase (AChE) and non-specific cholinesterase (BuChE). Except for iso-OMPA which is specific for BuChE localized in the microvessels endothelium, all the OP doses used in the present study were more or less potent inhibitors of cholinesterases (ChE). 15 mn after LD 50 doses of OP administered by subcutaneous route, a partial inhibition of the neurophile AChE occurred, revealing some striatal neurons which displayed high residual activity, i.e. the cholinergic interneurons. During the recovery phase following the inhibition of AChE by 1.5 LD 50 doses (the animals being treated with atropine) the AChE reaction product was detected almost simultaneously in some axo-spinous synapses probably non-cholinergic. The partial inhibition and the de novo synthesis of AChE also revealed the presence of small and less reactive non-cholinergic neurons. Among all the OP tested, soman was remarkable for its patchy inhibition of AChE in the striatum. The significance of the alternation of reactive and non-reactive areas is discussed.
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PMID:[Organophosphorus compounds as tools for the pharmaco-histochemical study of cholinesterase in the rat striatum]. 363 54

The localization of acetylcholinesterase (AChE) was investigated at the cellular and subcellular levels in dissociated cell cultures of the carotid body of the neonatal rat, prepared by the methods of Fishman and Schaffner (1984). In the presence of iso-OMPA, which blocks nonspecific cholinesterase, staining was confined almost exclusively to glomus-cell clusters and occasional isolated cells. These clusters grow as discrete islands scattered throughout the culture and display typical catecholamine (CA) fluorescence as in vivo. AChE staining was abolished or reduced by the cholinesterase inhibitors eserine (30-100 microM), or (the poorly lipid soluble) echothiophate (8 microM). Processing of the same culture sequentially for the demonstration of both AChE and CA revealed that glomus-cell clusters and individual glomus cells were consistently positive for both. In electron micrographs AChE reaction product was associated intracellularly with the nuclear envelope and cytoplasm of glomus cells (identified by their characteristic dense cored granules), as well as extracellularly with the boundaries of contiguous glomus cells. Significantly, reaction product occurred in some glomus cell profiles that had both dense-cored and clear (cholinergic-like) vesicles. These findings are discussed in the context of a possible dual (adrenergic/cholinergic) function status of glomus cells in the rat's carotid body.
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PMID:Localization of acetylcholinesterase in dissociated cell cultures of the carotid body of the rat. 365 61

The expression of muscarinic acetylcholine binding sites and of cholinesterases was studied in extracts prepared from discrete regions of the human fetal brain, between the gestational ages of 14 and 24 weeks. The specific binding of [3H]N-methyl-4-piperidyl benzilate [( 4H]-4NMPB) to muscarinic binding sites ranged between 0.05 and 1.30 pmol/mg protein in the different brain regions, with Kd values of 1.2 +/- 0.2 nM. Binding of the cholinergic agonist oxotremorine fitted, in most of the brain regions examined, with a two-site model for the muscarinic binding sites. The density of muscarinic binding sites increased with development in most regions, with different rates and onset times. It was higher by about sixfold in some areas destined to become cholinergic, such as the cortex and midbrain, than in noncholinergic areas such as the cerebellum. In other areas destined to become cholinergic, such as the hippocampus and the caudate putamen, the receptor density remained low. Average density values increased from 0.1 +/- 0.1 at 14 weeks up to 0.7 +/- 0.4 pmol/mg protein at 24 weeks. The variability in the specific activities of cholinesterase was relatively low, and extracts from different brain regions hydrolyzed from 5 to 30 nmol of [3H]acetylcholine/min/mg protein. These were mostly "true" acetylcholinesterase (EC 3.1.1.7) activities, inhibited by 10(-5) M BW284C51, with minor pseudocholinesterase (EC 3.1.1.8) activities, inhibited by 10(-5) M iso-OMPA. The enzyme from different brain regions and developmental stages displayed similar Km values toward [3H]acetylcholine (ca. 4 X 10(-4) M-1). The ontogenetic changes in cholinesterase specific activities had no unifying pattern and/or relationship to the cholinergic nature of the various brain areas. In most of the brain regions, the arbitrary ratio between the specific activity of cholinesterase and the density of muscarinic binding sites decreased with development, with average values and variability ranges of 83 +/- 50 and 19 +/- 19 at 14 and 24 weeks, respectively. Our findings suggest divergent regulation for cholinergic binding sites and cholinesterase in the fetal human brain and imply that the expression of muscarinic receptors is related to the development of cholinergic transmission, while acetylcholinesterase is also involved in other functions in the fetal human brain.
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PMID:Divergent regulation of muscarinic binding sites and acetylcholinesterase in discrete regions of the developing human fetal brain. 371 20

Rats treated daily with diisopropylfluorophosphate (DFP) (0.5 mg/kg, sc), an inhibitor of acetylcholinesterase (AChE) activity, exhibited the symptoms of cholinergic hyperactivity between Days 3 and 5 similar to those observed 15 min after a single acute dosage (1.5 mg/kg, sc). A significant (p less than 0.05) decrease in the activities of both AChE and cholinesterase (BuChE) (greater than 80%) occurred in muscles and in brain regions and of aliesterases in liver (greater than 92%) at this time. Further administration of DFP (0.5 mg/kg, for 7-14 days) led to behavioral tolerance, where symptoms of toxicity disappeared such as muscle fasciculations, tremors, and muscle necrosis. The activity of aliesterases in liver and AChE in muscles significantly (p less than 0.01) recovered, while no such recovery was seen in brain AChE. DFP toxicity was potentiated in rats that were pretreated with BuChE inhibitors, such as iso-OMPA (3 mg/kg, sc) or mipafox (0.05 mg/kg, sc), 30 min prior to DFP (0.5 mg/kg, sc). The severity of cholinergic hyperactivity and inhibition of aliesterase in liver, AChE and BuChE activity in brain and muscles was greater when compared to the effects of DFP alone. Both iso-OMPA and mipafox completely abolished the tolerance development to DFP, since no animal survived more than 5 days of combined treatment. The observed adaptation to DFP toxicity appears to be due to recovery of aliesterase, BuChE, and AChE activity as well as decreased nicotinic binding sites at the neuromuscular junction, as previously reported.
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PMID:Mechanisms involved in the development of tolerance to DFP toxicity. 409 85

1 Isolated, desheathed preparations of the rabbit rectococcygeus muscle were relatively insensitive to spasmogens other than muscarinic drugs. Transmural stimulation with 1-50 pulses (0.2-0.4 ms at 10 Hz) elicited graded twitches which were abolished by tetrodotoxin and were therefore neurogenic; longer pulses sometimes triggered tetrodotoxin-resistant myogenic contractions.2 Twitches elicited by 0.2-0.4 ms pulses were due to post-ganglionic excitation because they were not reduced by hexamethonium, pentolinium or dimethyltubocurarine, or by ganglion-paralyzing concentrations of nicotine.3 The acetyl- and butyryl-cholinesterase activities of the rectococcygeus were determined manometrically and could be selectively inhibited by BW 284C51 (1:5-bis-(4-allyl-dimethylammonium-phenyl)-pentan-3-one dibromide) and iso-OMPA (tetramonoisopropylpyrophosphortetramide), respectively. Single-pulse twitches were greatly potentiated in amplitude and duration only when both cholinesterases were inhibited.4 The preparations could not be made to contract by nicotine (2.1-21 muM) even after cholinesterase inhibition, suggesting an absence of ganglion-cells; with nicotine (105-210 muM) small, atropine-susceptible responses were elicited, which were non-ganglionic because they were not reduced by tetrodotoxin.5 Rectococcygeus preparations that had been treated with physostigmine released acetylcholine into the bath fluid on electrical stimulation.6 The motor transmission was paralyzed by botulinum toxin (Type A) and abolished by atropine; the block of muscarinic receptors by atropine was effective against both endogenous and exogenous acetylcholine.7 Inhibitory adrenoceptors and scanty motor alpha-adrenoceptors were detected in the smooth muscle.8 Strong inhibitions of motor transmission and of rhythmic activity were produced by noradrenaline (but not by tyramine), by isoprenaline, and, after phentolamine, also by adrenaline and phenylephrine. These inhibitions were only slightly reduced by propranolol and rather more by pindolol.9 Experiments on preparations retaining their extrinsic nerve supply suggest an absence of ganglionic relays in the last 1-2 cm of the motor nerve pathway to this muscle.10 Some contrasting properties of the adjacent caudo-anal muscle, including the poor motor responses to transmural stimulation, are described.
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PMID:The rabbit rectococcygeus: a ganglion-free parasympathetically innervated preparation. 415 88

1. The neuromuscular blocking action of suxamethonium, given by intravenous injection, and the effect upon it of iso-OMPA (tetraisopropyl pyrophosphoramide) in doses which produced marked selective inhibition of cholinesterase in blood were studied in anaesthetized rats and cats, and in mice.2. In cats experiments were also carried out in which suxamethonium was given by intravenous infusion until an effect which remained constant with time was achieved. From the degree of neuromuscular block (under equilibrium conditions) obtained with different infusion rates the infusion rate for 50% reduction in twitch tension of the indirectly stimulated soleus and gastrocnemius muscles (IR50) was calculated. The effect on it of raising the suxamethonium hydrolysing capacity of blood and of selectively reducing the level of cholinesterase in blood by various doses of iso-OMPA was then investigated.3. At relevant stages of each experiment cholinesterase activity in blood was determined with butyrylcholine or benzoylcholine and where appropriate with suxamethonium as substrate.4. The results obtained show that in rats and cats the effectiveness of suxamethonium is unrelated to the level of cholinesterase activity in blood and that raising the suxamethonium hydrolysing capacity in the blood up to 22-fold (in cats) only reduces the IR50 by a factor of 1.6.5. The enhancement of the effectiveness of suxamethonium in the three species (2- to 3-fold in rats, 2- to 4-fold in mice and 7- to 8-fold in cats under the conditions used for comparison) which follows the administration of iso-OMPA is attributable to inhibition of cholinesterase in the tissues.6. It is concluded that the results obtained clearly indicate that the species studied do not give information as regards suxamethonium and its metabolism which is applicable to man.
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PMID:The relationship between the level of cholinesterase in plasma and the action of suxamethonium in animals. 432 43


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