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)

A death due to ingestion of 2,4-dichlorophenoxyacetic acid (2,4-D), 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP), and phosphorothioic acid O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl)ester (chlorpyrifos) is reported. The clinical course, dose ingested, and plasma levels of the chemicals were compatible with previous fatalities due to the chlorophenoxyacetic acids. Chlorpyrifos concentrations and tissue cholinesterase and in esterase inhibitions indicated the presence of the organophosphate and its biochemical effect, but few cholinergic signs were observed clinically. Lymphocytic neurotoxic esterase activity was decreased for a limited period of time after ingestion. Postmortem nervous tissue neurotoxic esterase was also decreased. This association has not been demonstrated before in man. HPLC and GC/NPD methods for measuring chlorophenoxy acetic acids and chlorpyrifos, respectively, are presented.
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PMID:Toxicologic studies in a fatal overdose of 2,4-D, MCPP, and chlorpyrifos. 619 35

Male rats were treated for 10 days with the organophosphorus insecticide, acetylcholinesterase inhibitor, O,O-diethyl S-[2-(ethylthio)ethyl] phosphorodithioate (disulfoton, 2 mg/kg/day by gavage). At the end of the treatment, binding of [3H]quinuclidinyl benzilate ( [3H]QNB) to cholinergic muscarinic receptors and cholinesterase (ChE) activity were assayed in the pancreas. Functional activity of pancreatic muscarinic receptor was investigated by determining carbachol-stimulated secretion of alpha-amylase in vitro. ChE activity and [3H]QNB binding were significantly decreased in the pancreas from disulfoton-treated rats. The alteration of [3H]QNB binding was due to a decrease in muscarinic receptor density with no change in the affinity. Basal secretion of amylase from pancreas in vitro was not altered, but carbachol-stimulated secretion was decreased. The effect appeared to be specific since pancreozymin was able to induce the same amylase release from pancreases of control and treated rats. The results suggest that repeated exposures to sublethal doses of an organophosphorus insecticide lead to a biochemical and functional alteration of cholinergic muscarinic receptors in the pancreas.
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PMID:Chronic administration of an organophosphorus insecticide to rats alters cholinergic muscarinic receptors in the pancreas. 660 6

Tolerance to the toxic signs of the organophosphorus ester acetylcholinesterase inhibitor, O,O-diethyl S-[2-(ethylthio)ethyl] phosphorodithioate (disulfoton), was induced in rats by giving 10 doses of 2.0 mg/kg/day. Concurrent with the induction of tolerance, decreased sensitivity to the cholinergic agonists carbachol and oxotremorine could be demonstrated in studies of heart rate in vivo and in isolated preparations of ileum and atria. A significant decrease in the binding of the muscarinic antagonist [3H]quinuclidinyl benzilate could be demonstrated in ileum from disulfoton-tolerant animals. However, no alterations in the binding of [3H]quinuclidinyl benzilate, [3H]oxotremorine-M, or oxotremorine were evident in atria from tolerant animals. The results suggest that, in addition to receptor loss, other mechanisms distal to ligand recognition sites or removed from the receptor complex may contribute to the subsensitivity of tissues to muscarinic cholinergic agonists.
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PMID:Muscarinic receptor alterations as a mechanism of anticholinesterase tolerance. 663 79

The effect of atropine, 2-pyridine aldoxime methiodide (2-PAM), and several O,O,O-trialkylphosphorothioates on poisoning of rats by a series of O,O-dimethyl and O,O-diethyl S-alkyl phosphorothioates was investigated. Atropine and 2-PAM successfully protected rats treated with O,O-diethyl S-n-propyl and S-i-propyl phosphorothioates, while the O,O,O-trialkyl phosphorothioates were effective in protecting rats treated with O,O-dimethyl S-methyl and S-ethyl phosphorothioates. O,O-Dimethyl and O,O-diethyl S-i-propyl phosphorothioates also were examined for in vitro and in vivo inhibition of rat plasma, red blood cell, and brain cholinesterase. Overall, the results indicated that two different mechanisms, cholinergic and noncholinergic, are involved in intoxication by the O,O,S-trialkyl phosphorothioates.
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PMID:Toxicological properties of O,O,S-trialkyl phosphorothioates. 666 10

Carboxylesterases (EC 3.1.1.1) of chicken brain were investigated by applying kinetic analysis of organophosphorus inhibition. By iterative elimination of exponential inhibition curves and by sequential inhibition experiments using a combination of two organophosphorus inhibitors, 11 different carboxylesterases of chicken brain were characterized with respect to their phenyl valerate-hydrolyzing activity (milliunits per gram of brain) and their inhibition by O,O-diethyl O-4-nitrophenyl phosphate (Paraoxon), O,O-diisopropylphosphorofluoridate, and N,N'-diisopropylphosphorodiamidic fluoride (Mipafox). The bimolecular inhibition rate constants (liters . mole-1 . min-1) were calculated for the 11 enzymes and 3 organophosphorus compounds. The corresponding data for acetylcholinesterase (EC 3.1.1.7) in chicken brain were determined. The importance of inhibition rate constants for the development of acute cholinergic symptoms, delayed neurotoxicity, and atypical organophosphate effects is shown.
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PMID:Inhibition of brain carboxylesterases by neurotoxic and nonneurotoxic organophosphorus compounds. 686 14

Previous work from this laboratory revealed in increased canine pancreatic intraductal pressure following cholinesterase inhibitor intoxication. The pressure was negatively correlated with serum butyrylcholinesterase (BChE) activity, suggesting that BChE activity mediated the pressure rise. This study uses a histochemical technique to investigate the tissue cholinesterase activity of the canine pancreatic sphincters and the effect of a cholinesterase inhibitor (ChEI) on tissue cholinesterase activity. In five control dogs, serial sections of the major and minor spincters were stained for acetylcholinesterase (AChE) and BChE activity. Four treated dogs were given the ChEI, O,O-diethyl-O- (2-isopropyl-6-methyl-4-pyrimidinyl) phosphoro-thioate, 25 mg/kg, one hour prior to excising the ampullae. In the control dogs, BChE activity is present in the periampullary nerves and the pancreatic smooth muscle sphincters. AChE activity is present in nerves but not in smooth muscle. In the treated group, following a dose of ChEI known to cause ductal hypertension, BChE activity was absent in the pancreatic sphincters but AChE activity was preserved in the periampullary nerves. These data suggest that the pancreatic ductal hypertension that occurs following ChEI administration is due to a selective reduction in pancreatic smooth muscle BChE activity.
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PMID:A study of the cholinesterases of the canine pancreatic sphincters and the relationship between reduced butyrylcholinesterase activity and pancreatic ductal hypertension. 743 91

Although the acute effects of organophosphorus esters are generally ascribed to inhibition of acetylcholinesterase, work in this laboratory and others indicates that organophosphorus insecticides also interact directly with cholinergic receptors. The current study verifies that the insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothionate (chlorpyrifos) and its oxon metabolite inhibits acetylcholinesterase (AChE). The metabolite inhibits rat brain AChE three orders of magnitude more rapidly than chlorpyrifos. In addition to their ability to inhibit AChE, these compounds were shown to interact directly with muscarinic receptors of rat striatum. The oxon metabolite bound at low concentrations to muscarinic receptors labeled by the muscarinic agonist [3H] cis-methyldioxolane; chlorpyrifos oxon bound with an IC50 value of 22.1 +/- 3.6 nM. The receptors bound by chlorpyrifos oxon account for approximately 30% of muscarinic receptors of the striatum and are of the m2 subtype. The binding of chlorpyrifos oxon to the m2 receptor results in a covalent modification of the receptor that does not interfere with the ability of the receptor to interact with the agonist carbachol. This receptor modification may be responsible for the inhibition of adenylate cyclase activity by chlorpyrifos oxon. The oxon inhibited adenylate cyclase with an IC50 of 155 +/- 78 nM. The inhibition of adenylate cyclase activity was not blocked by atropine and was additive to that produced by carbachol. The altering of postreceptor signal transduction by chlorpyrifos oxon may interfere with normal cellular signaling, thereby disturbing neurological function. Direct interaction of chlorpyrifos oxon with muscarinic receptors and associated signal transduction is a potential mechanism of neurotoxicity that is independent of AChE inhibition.
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PMID:Chlorpyrifos oxon binds directly to muscarinic receptors and inhibits cAMP accumulation in rat striatum. 751 60

Although the neurotoxicity of organophosphorus compounds is generally attributed to inhibition of acetylcholinesterase, recent reports have indicated that direct interactions with muscarinic receptors and signal transduction may be an additional mechanism of neurotoxicity. We have previously shown that the organophosphorus insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate (chlorpyrifos) binds directly to muscarinic receptors and inhibits adenylate cyclase of rat striatum. We have further pursued those results in this study by investigating the effect of chlorpyrifos oxon in NG108-15 neuroblastoma-glioma cells and Chinese hamster ovary cells transfected with cDNA for human m2 or m4 muscarinic receptor subtypes. At millimolar concentrations, chlorpyrifos oxon inhibited [3H]QNB binding in all cell lines. Likewise, [3H]CD binding was inhibited in NG108-15 and CHO-Hm2 cells. When the effect of chlorpyrifos oxon on adenylate cyclase was examined, the oxon was found to inhibit adenylate cyclase at millimolar concentrations. Though this effect on cyclase required greater concentrations of oxon than the comparable effect in striatal cells, it displayed the common characteristic of being atropine-insensitive, suggesting that the effect on cyclase was not muscarinic receptor dependent. The inhibition of adenylate cyclase produced by chlorpyrifos oxon was not eliminated in pertussis toxin treated cells, lending further support to the idea that it is not a receptor-mediated event, and suggesting a potential direct interaction of chlorpyrifos oxon with the adenylate cyclase molecule.
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PMID:In vitro effect of chlorpyrifos oxon on muscarinic receptors and adenylate cyclase. 756 87

Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: application to assessment of neuropathic risk. 768 90

We studied the ability of 2-PAM to reactivate cholinesterase (ChE) inhibited by organophosphorus compounds (OPs) and aging. We estimated the reactivation rate with 2-PAM following inhibition of ChE by fenitrothion, methylparathion or ethylparathion using erythrocytes of rat and rabbit and rat brain. The period of time during which inhibited ChE could be reactivated was shorter in the case of inhibition by fenitrothion or methylparathion than in the case of inhibition by ethylparathion. This results suggest that aging is related to the presence of the alkyl group in OPs, and occurs faster in the case of inhibition by OPs with an O,O-dimethyl moiety than in the case of inhibition by OPs with an O,O-diethyl moiety.
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PMID:Studies on the therapeutic effect of 2-pyridine aldoxime methiodide (2-PAM) in mammals following organophosphorus compound (OP)-poisoning (report II): aging of OP-inhibited mammalian cholinesterase. 824 10


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