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 first kinetic studies on the spontaneous reactivation of Sarin-inhibited acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) are reported. With increasing pH the extent of reactivation increases while the observed rate constant decreases. An analysis of the change in aging rate constant as a function of pH suggests that the aging of alkyl-alkoxy phosphonylated acetylcholinesterases is not solely acid catalyzed.
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PMID:Spontaneous reactivation of acetylcholinesterase following organophosphate inhibition. I. An analysis of anomalous reactivation kinetics. 1 68

1. The effects of a range of organophosphorus anticholinesterases on the nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. Diisopropylfluorophosphate (DFP), sarin and soman had no effect on open times at concentrations of up to 100 microM, but ecothiopate (Eco) and O-ethyl S-[2-(diisopropylamino)ethyl]methyl phosphonothiolate (VX) were found to have voltage- and concentration-dependent open channel-blocking actions at concentrations of 1-50 microM. In addition to its channel-blocking action, Eco (50 microM) had a weak agonist effect: it is suggested that this may be attributable to thiocholine produced by hydrolysis of Eco. 2. Rate constants for blockade by Eco and VX were determined according to a sequential model. The greater voltage-dependence of the block by Eco was due to a greater voltage sensitivity of the blocking rate constant compared to VX: the voltage-dependence of the unblocking rate constant was similar for both compounds. 3. In control recordings, the frequency of channel opening declined exponentially with time after formation of the gigaseal. Sarin and soman both increased the rate of this decline, indicating that they accelerated the rate of desensitization of the receptors. Eco and VX reduced the initial frequency of opening, which may have been due to enhancement of a fast phase of desensitization during gigaseal formation, or to blockade of closed channels. 4. It is concluded that the direct actions of organophosphates on nicotinic receptor ion channels are of little importance for their toxicity under normal conditions, since they occur only at much higher concentrations than those which cause inhibition of acetylcholinesterase. Such actions may become apparent, however, when therapies against the anticholinesterase effects of organophosphates increase their lethal dose sufficiently. These direct actions should also be taken into account when the effects of organophosphates on cholinergic transmission are studied.
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PMID:Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates. 170 77

In human volunteers, studies to assess the adverse effects of the carbamate anticholinesterase physostigmine showed that the intramuscular dose observed to induce emesis in 50% of subjects tested (ED50) was 28.1 (23.5-120.7) micrograms/kg. This dose reduced whole blood cholinesterase (ChE) activity to 60% of control values. Studies in marmosets to assess the behavioural toxicology of physostigmine showed that the corresponding ED50 and ChE activity values were 34.3 (21.5-55.8) micrograms/kg and 66% respectively. Sarin was also shown to induce emesis in marmosets, but only at doses that reduced erythrocyte ChE activity to 12% of control values. These data seem also to correspond with reports of organophosphate poisoning in humans. It is concluded that the marmoset may be a very good model of both carbamate and organophosphate-induced emesis in humans.
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PMID:A model for carbamate and organophosphate-induced emesis in humans. 190 98

The effect of Soman, Sarin and Vx, known potent cholinesterase inhibitors, on the binding of several neurotransmitter receptors in various regions of brain was studied. Vx, exhibited considerable inhibition of binding of 3H-N-methylscopolamine (3H-NMS) to muscarinic receptors and of 3H-spiperone to dopamine D2 receptors in the striatum. 3H-NMS binding was 50% inhibited at 10(-6)M and 90% at 10(-3)M Vx. Inhibition of 3H-spiperone binding by Vx in striatum had an ID50 of 10(-5)M. KD of the treatment was affected more than Bmax. Binding inhibition of both 3H-NMS and 3H-spiperone in post-mortem brain of rats pre-treated with Vx confirmed the specificity of the organophosphates effect, since other organophosphates and ligands failed to show any activity.
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PMID:Effect of organophosphates on dopamine and muscarinic receptor binding in rat brain. 214 Dec 56

The effects on behaviour of single subtoxic doses of two potent organophosphorous compounds, sarin (isopropyl methylphosphonofluoridate, 12.5 and 50 micrograms/kg, intraperitoneally) and soman (pinacolyl methylphosphonofluoridate, 4 and 20 micrograms/kg, intraperitoneally) were studied in male Wistar rats. In the open field test, soman dose-dependently decreased rearing and ambulation and increased non-mobile exploration. The higher dose of sarin changed only the rearing and grooming behaviour. Sarin and soman decreased locomotor activity on the Animex for at least one hour at the beginning of the monitoring period. In the doses used, both organophosphates inhibited acetylcholinesterase (AChE) activity significantly in the blood. The results suggest that small doses of sarin and soman have inactivating effects on the behaviour of rats. Although the findings cannot be extrapolated directly to behavioural changes in man, they indicate that subtle behavioural dysfunctions could also occur in humans at exposures which do not cause acute toxicity.
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PMID:Acute behavioural effects of the organophosphates sarin and soman in rats. 239 14

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.
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PMID:Neuropathy target esterase in hens after sarin and soman. 276 93

Squid nerve contains an enzyme that hydrolyzes the nerve gas Tabun at about one-tenth the rate it hydrolyzes diisopropylphosphorofluoridate (DFP), and at about one-third to one-fourth the rate it hydrolyzes Sarin and Soman. Tabun is a more potent inhibitor of acetylcholinesterase than is DFP, is both lipid-and water-soluble, and penetrates readily into the squid giant axon in its inhibitory form. The failure of Tabun to block or markedly decrease the conducted action potential in the squid axon makes it likely that the blocking of conduction caused by DFP is probably not due to inhibition of acetylcholinesterase. Sub-strate specificity with regard to organophosphate metabolism by squid enzyme has possible implications for the disposal and detoxication of nerve gases in the ocean.
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PMID:Diisopropylphosphorofluoridate and Tabun: enzymatic hydrolysis and nerve function. 557 58

The sc LD50s (mumol/kg) in rats for diisopropylfluorophosphate (DFP), Tabun, Sarin, and Soman were 14.5, 1.9, 1.4, and 0.88, respectively. The relative potency was as follows: DFP less than Tabun less than Sarin less than Soman (1:7.6:10.4:16.4). The relative potencies correlated with the in vitro acetylcholinesterase (AChE) inhibition (in terms of the IC50) by these compounds, in whole brain homogenates or the purified bovine erythrocyte AChE. There was a dose versus time for mortality relationship for all four compounds; the average time for death decreased with increase in dose. However, there was no correlation between time for death and the extent of AChE inhibition. The striatal as well as other regional (medulla, diencephalon, cortex, and cerebellum) AChE activity was inhibited over 90% of the control, by the lethal doses of these compounds. None of the lethal or sublethal doses had any apparent effect on choline acetyltransferase (CAT) or GABA-transaminase activities. Glutamic acid decarboxylase activity was increased by Soman, Sarin, and Tabun at certain lethal doses but was not affected by DFP even at the lethal dose. The results indicate that (a) the acute toxicity of organophosphate acetylcholinesterase inhibitors is directly related to the inhibition of AChE though there is a wide difference in their potency; (b) a substantial inhibition of AChE activity (over 90% of control) is necessary for lethality to ensue after an acute exposure and the margins between lethal and nonlethal doses are extremely small; and (c) qualitative differences seem to exist among the various organophosphates in affecting noncholinergic neurotransmitter enzymes.
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PMID:An assessment of comparative acute toxicity of diisopropyl-fluorophosphate, tabun, sarin, and soman in relation to cholinergic and GABAergic enzyme activities in rats. 647 98

In atropine-pretreated rats, HI-6 (125 mg/kg i.p.) raised the LD50 of Soman (subcutaneous) 5.7 times. Addition of HI-6 (25 micrograms i.c.v.) failed to enhance this protection further. HI-6 (intraperitoneal) also protected animals from intracerebroventricular Soman. HI-6, administered intracerebroventricularly either alone or in combination with intraperitoneal HI-6, failed to increase protection, nor did it reactivate Soman-inhibited acetylcholinesterase (AChE) in several brain areas. HI-6 (125 or 62.5 mg/kg i.p.) protected rats from Sarin lethality, but only the higher dose significantly altered the brain AChE activity. Furthermore, HI-6 (intraperitoneal) failed to block the Soman-induced increase in acetylcholine (ACh) or choline (Ch) levels in any of the brain areas examined. These data indicate that HI-6 is a very beneficial therapy against Soman, but that no definitive central anticholinergic activity of the compound could be found to explain its protective effects. It is possible that HI-6 acts by noncholinergic central mechanisms, or that it produces its beneficial effects outside the CNS. Furthermore, brain AChE activity does not appear to be indicative of protective effects of this oxime. ACh or Ch levels in this study were not good parameters to predict the outcome of Soman poisoning.
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PMID:Examination of the role of central cholinergic mechanisms in the therapeutic effects of HI-6 in organophosphate poisoning. 683 63

HI-6 was the least toxic and the most efficacious oxime examined against Soman poisoning with a high safety ratio between 26-30. Reactivation of peripheral acetylcholinesterase following Soman poisoning was more important in the beneficial therapeutic action of HI-6 than reactivation of central acetylcholinesterase. HI-6 reactivated Sarin-inhibited but not Tabun-inhibited acetylcholinesterase both peripherally and centrally. HI-6 passes the blood brain barrier as evidenced by its reactivation centrally of Sarin-inhibited acetylcholinesterase. Soman-inhibited enzyme was not aged in vivo by 30 min. In vivo diaphragm acetylcholinesterase was inhibited to a greater extent by Soman, Sarin and Tabun than intercostal muscle acetylcholinesterase. In vitro diaphragm and intercostal muscle acetylcholinesterase had similar IC50 values for Soman. HI-6 has antimuscarinic and antinicotinic activity in addition to its previously reported ganglion blocking activity (Lundy and Tremblay, 1979). These additional pharmacological actions of HI-6 may play a role in the therapeutic action of HI-6 (at the higher concentrations). The results suggest that peripheral acetylcholinesterase in the rat diaphragm is the primary lesion in Soman poisoning. The beneficial action of HI-6 in rats versus Soman poisoning is due to reactivation of diaphragm acetylcholinesterase.
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PMID:Toxicology and pharmacology of bispyridium oximes--insight into the mechanism of action vs Soman poisoning in vivo. 689 46


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