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 effect of chronic administration of diisopropylphosphorofluoridate (DFP) on the levels and forms of plasma cholinesterase (ChE), were studied in male Wistar albino rats sacrificed at different time intervals after various schedules of treatment. In particular the inhibition and recovery rate of the enzymatic activity was evaluated for butyrylcholinesterase (BuChE), determined using butyrylthiocholine (BuThCh) as substrate and for acetylcholinesterase (AChE), measured using acetylthiocholine (AcThCh) in the presence of iso-OMPA 0.1 mM. At 1 1/2 and 24 hr after the DFP treatments, BuChE was considerably more depressed than was the case for AChE. Moreover, the recovery of BuChE proceeded more slowly, its activity being restored only seven days after the last treatment, while the recovery of AChE was completed 72 hr after the end of the treatments. Plasma molecular forms were separated by polyacrylamide gel electrophoresis and were revealed by enzymatic reaction with BuThCh or AcThCh as substrates. By using selective inhibitors, five main molecular forms of BuChE and two of AChE were found to exist in control plasma samples. A differential inhibition and recovery rate was observed among these forms after DFP intoxication. At 1 1/2 hr after the treatments, the BuChE activity was too low to be detected on the gels, but 24 hr thereafter, the quantitative determination of the different forms, performed by scanning densitometry, showed a significant increase of the two faster migrating ones. At the following time intervals, the electrophoretic pattern returned progressively towards normality. The faster migrating forms are therefore probably the first synthesized in the process of recovery of BuChE activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication. 670 81

The topographical distribution of neurons containing acetylcholinesterase (AChE, EC 3.1.1.7) in the basal forebrain and upper brainstem of the squirrel monkey (Saimiri sciureus) was studied by means of Butcher's pharmacohistochemical technique which involves staining for AChE at various times after the systemic administration of the AChE inhibitor di-isopropylphosphorofluoridate (DFP). Only those neurons whose AChE staining was as intense as that of known cholinergic neurons present in the same material (e.g., neurons of cranial nerve nuclei) were examined and mapped. Three major collections of such strongly-stained AChE neurons were disclosed in squirrel monkey brain: one located in the striatum, the other lying along the ventralmost aspects of the basal forebrain, and a third one present within the midbrain-pontine tegmentum. The striatal AChE neurons vary in shape from fusiform with 2 thick processes to polygonal with 4-5 thinner processes. They are uniformly scattered throughout the caudate nucleus and putamen and represent only a small proportion of the total striatal cell population (4-6 cells/mm2). They most likely correspond to the aspiny type II cells described in Golgi material of monkey striatum. Similar neurons occur also in ventral striatal areas comprising nucleus accumbens septi and the deep polymorph layer of the olfactory tubercle. The second major AChE neuronal population is composed of the magnocellular neurons that form a somewhat continuous chain of neuronal aggregates extending rostrocaudally from the septal region to the caudal pole of the lentiform nucleus. It includes the neurons of the medial septal nucleus, the nucleus of the diagonal band of Broca and the nucleus basalis of Meynert, all displaying strikingly similar morphological and histochemical characteristics. The AChE neuronal population of nucleus basalis encroaches markedly upon the lateral hypothalamus laterally and the globus pallidus dorsally. The third important AChE cell collection occurs within the pedunculopontine nucleus area in upper brainstem. In that constellation, the AChE neurons are clustered in 2 continuous cell groups: one located dorsolaterally, the other lying ventromedially to the brachium conjunctivum. The thick processes of these neurons form impressive AChE neuronal networks that surround and pervade the brachium conjunctivum over long distances. This cell group, which is one of the most highly AChE reactive structures of the entire brain in the squirrel monkey, may provide a major cholinergic input to various basal ganglia structures, particularly the substantia nigra.
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PMID:Distribution of acetylcholinesterase-containing neurons in the basal forebrain and upper brainstem of the squirrel monkey (Saimiri sciureus). 671 15

The toxicity of trichlorfon (O,O-dimethyl-2,2,2,-trichloro-1-hydroxyethylphosphonate, Dipterex, Dylox), reported to elicit delayed neurotoxicity in man and chickens, was studied by administering single subcutaneous doses of 100 or 300 mg/kg to adult White Leghorn hens. At 24 h posttreatment, the birds were observed for visible signs of neurotoxicity, were euthanized, and samples of blood plasma, brain, and spinal cord (cervical and thoracic regions) were obtained for quantification of cholinesterase and neurotoxic esterase (NTE) activities. In subacute studies, hens were dosed with trichlorfon (100 mg/kg) every 72 h for a total of six doses. Seventy-two hours after the final dose the hens were euthanized, the brains, spinal cords, and distal sciatic nerves were removed for enzymatic and (or) histological examination. Parallel acute and subacute studies were conducted using diisopropyl phosphorofluoridate (DFP), a known neurotoxic agent, at subcutaneous dosages of 1.0 mg/kg. In the acute studies, both DFP and trichlorfon markedly inhibited tissue cholinesterase activities but only DFP elicited a significant inhibition of NTE. In the subacute studies, DFP produced a characteristic central-peripheral distal axonopathy in the 18-day period of study which was confirmed by clinical and morphological evidence and by marked inhibition of neuronal NTE. Trichlorfon caused little or no obvious neurotoxicity, an observation that was supported by minimal morphological changes and impairment of walking ability and no inhibition of brain or spinal cord NTE.
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PMID:An acute and subacute neurotoxicity assessment of trichlorfon. 673 96

The number of catalytic subunits of purified bovine nucleus caudatus acetylcholinesterase (E.C. 3.1.1.7) has been determined by active site labelling with [3H]diisopropyl fluorophosphate ([3H]DFP). The 10.5 S, 16 S, and 20 S forms were estimated to contain two, four, and six active sites, respectively, per molecule. A 4.8 S form, which showed a weak amphiphile-dependent activity behavior, was obtained by selective proteolytic digestion with pronase. The inability of the purified 4.8 S form to aggregate after detergent removal, and the molecular mass in the range of 130-165 kD under nondenaturating conditions, indicate that this form is a dimeric form, lacking those hydrophobic regions responsible for aggregation.
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PMID:Bovine nucleus caudatus acetylcholinesterase: active site determination and investigation of a dimeric form obtained by selective proteolysis. 674 36

1 Twitch potentiation produced by anticholinesterases has been variously attributed to the prolonged postjunctional action of acetylcholine (ACh), a prejunctional action of ACh involving the initiation of antidromic firing (ADF) in the nerve or a direct action of the anticholinesterases on nerve terminals initiating ADF. 2 The organophosphate anticholinesterases, paraoxon (diethyl-4-nitrophenylphosphate) and DFP (diisopropyl fluorophosphate), when applied to rat isolated diaphragm preparations for 30 min, produced twitch potentiation which subsequently declined. 3 The rates of onset and decline of twitch potentiation were directly related to the concentration of the organophosphates and the reversibility of their effects was in line with the reactivation of the phosphorylated enzymes formed by them, whether reactivation was spontaneous or induced by the oxime, N,N'-trimethylene-1, 3-bis(pyridinium-4-aldoxime). 4 Reducing the output of ACh from nerve terminals (by reducing the ratio of calcium: magnesium ions in the bathing solution) or reducing the affinity of ACh for the nicotinic cholinoceptor (using the disulphide bond reducing agent, dithiothreitol) produced the same effects as did lowering the concentration of the organophosphates. 5 It is concluded that the twitch potentiation produced by paraoxon and DFP, and its failure to be maintained when the higher concentrations of the organophosphates were used, were the direct result of the excess of ACh in the synaptic cleft, following inhibition of acetylcholinesterase.
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PMID:Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations. 682 14

Cholinesterases in hen brain were characterized with respect to inhibition kinetics and substrate specificity. Three organophosphorus inhibitors were used: diethyl p-nitrophenyl phosphate (Paraoxon, E 600), di-isopropylphosphorofluoridate (DFP), and N,N'-di-isopropylphosphorodiamidic fluoride (Mipafox). The kinetics of irreversible cholinesterase inhibition were studied using two substrates, acetylthiocholine and butyrylthiocholine. The inhibition curves were analysed by the method of iterative elimination of exponential functions. Final classification of the different enzymes was done by combining two inhibitors in sequential inhibition expts. Six cholinesterases were shown to hydrolyse choline esters in hen brain, one was identified as acetylcholinesterase (EC 3.1.1.7) and one as cholinesterase (EC 3.1.1.8). Four enzymes can be classified as intermediate type cholinesterases according to their substrate specificity and to their inhibition constants. The possible role of different brain cholinesterases for the development of atypical symptoms following organophosphate intoxication is discussed.
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PMID:Brain cholinesterases. Differentiation of target enzymes for toxic organophosphorus compounds. 687 Sep 9

An enzyme purified from squid nerve that hydrolyzes the cholinesterase inhibitor diisopropyl phosphorofluoridate (DFP) has now been coupled to agarose beads. A column of this agarose-DFPase hydrolyzes the nerve gas 1,2,2-trimethylpropyl methylphosphonofluoridate (Soman). Although the more inhibitory of the four diastereoisomers of Soman are hydrolyzed least rapidly, a column of sufficient length will accomplish 95 percent hydrolysis whether measured by fluoride release or loss of cholinesterase-inhibiting power. The results suggest a means for detoxifying unwanted chemical warfare agents.
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PMID:Hydrolysis of nerve gas by squid-type diisopropyl phosphorofluoridate hydrolyzing enzyme on agarose resin. 705 44

In vitro studies showed that organophosphate insecticides have different IC50 values (i.e., concentration of inhibitor required to inhibit 50% enzyme activity) for acetylcholinesterases (AChE's) from different species. Since previous reports indicated that the binding of active cholinesterase inhibitors to non-critical binding proteins is an important mechanism of detoxification of organophosphate insecticides in vivo, we investigated the role of non-critical binding proteins in synaptosomal membrane preparations from monkey, rat and chicken brain tissues as a possible explanation of the differences in the IC50's. The amount of non-critical binding proteins as well as critical binding sites, AChE, were determined by 3H-DFP binding in vitro. The affinity constants (Ka) and phosphorylation constants (Kp) of DFP for AChE's from these preparations were also determined by kinetic studies. In IC50 studies, monkey brain AChE was 1.5X and 3.2X more sensitive to DFP inhibition than chicken and rat brain AChE. The observed differences in IC50's cannot be explained on the basis of differences in the amount of non-critical binding proteins, since only small amount of non-critical binding proteins were found in these preparations. However, in the kinetic studies, monkey brain AChE had 3.7X and 2.1X higher affinity than chicken and rat brain AChE, respectively; and chicken brain AChE had about 2.7X faster rate of phosphorylation than the other two. It is therefore concluded that non-critical binding proteins are relatively unimportant in terms of affecting IC50's. The differences observed in IC50's are primarily due to different affinity and/or rate of phosphorylation of AChE active sites by DFP.
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PMID:The role of non-critical binding proteins in the sensitivity of acetylcholinesterase from different species to diisopropyl fluorophosphate (DFP), in vitro. 712 Dec

The effect of two weeks of lithium (Li) pretreatment on up and down regulation of muscarinic receptors in rat brain was measured in two groups of rats. After two weeks of feeding 0.2% LiCL in ground pellets, one group of rats was injected with atropine (3 mg/kg daily for 5 days) and another group with diisopropyl fluorophosphate, a cholinesterase inhibitor (1.2 mg/kg). Li pretreatment completely abolishes the significant 23% rise in QNB binding induced by atropine but does not prevent the significant 16% decline in QNB binding induced by DFP. These results suggest that chronic Li pretreatment prevents supersensitivity but does not prevent subsensitivity of rat brain muscarinic receptors.
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PMID:The effect of chronic lithium pretreatment on rat brain muscarinic receptor regulation. 717 45

The effects of pyridine-2 aldoxime methyl iodide (PAM), N-methyl-1,6-dihydro-pyridine-2-carbaldoxime hydrochloride (proPAM), and diisopropyl phosphorofluoridate (DFP) on performance of a conditioned avoidance response (CAR), body temperature, and in vivo acetylcholinesterase (AChE) activity in five brain regions in the rat were examined. Sublethal doses of DFP (1.5 to 2.5 mg/kg, IP) markedly degraded CAR performance. This effect was antagonized by 5 mg/kg, subcutaneously injected (SC) atropine. A 50 mg/kg, SC dose of PAM had no effect on the CAR, but an equal dose of proPAM caused a transient deterioration of performance. Given 10 min or 2 hr after DFP, 50 mg/kg proPAM initially exacerbated the behaviorally toxic effects of DFP. Neither PAM nor proPAM antagonized DFP-induced hypothermia. PAM did not reactivate DFP-inhibited brain AChE, and proPAM reactivated it by only 6 to 12% of control activity.
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PMID:Effects of PAM, proPAM, and DFP on behavior, thermoregulation, and brain AChE in rats. 717 95


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