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 influence of genotypes of the major histocompatibility complex (MHC) on susceptibility to acute and delayed effects of an organophosphorus ester was measured in adult White Leghorn chickens from lines differing in response to sheep red blood cell (SRBC) antigen. Chickens from lines selected for high (HA) or low (LA) antibody response to SRBC and homozygous for B13B13 or B21B21 genotypes at the MHC were administered a single subcutaneous injection of diisopropyl phosphorofluoridate (DFP) at dosages of 0, 0.25, 0.50, or 1.0 mg/kg body weight using corn oil as the carrier. Criteria for toxicological responses included clinical, biochemical, and pathological measures. Clinical signs of acute cholinergic poisoning and delayed neuropathy were dose related. Brain and blood cholinesterase and carboxylesterase activities were more sensitive to inhibition by DFP than were liver cholinesterase and carboxylesterase activities. Cholinergic signs 3 h after administration of DFP were more pronounced in line HA than in line LA chickens. Pathological evidence of delayed neuropathy 2 wk after DFP administration was also more evident in HA than LA chickens. Although less pronounced than that for lines, differences in neurotoxic manifestations following DFP administration were greater for chickens of B21B21 than B13B13 genotypes. Activity of A-esterases, which hydrolyze organophosphorus esters without being inhibited by them, was lower in plasma of line HA than line LA chickens. Differences among the genotypes in activity of other esterases were not found in chickens not receiving DFP. These results indicated that responses of chickens to the neurotoxicant DFP were influenced by the background genome of the chickens.
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PMID:Differences between genetic stocks of chickens in response to acute and delayed effects of an organophosphorus compound. 834 37

The present review discusses the structure of the anticholinesterase organophosphates (OPs), which are used predominantly as insecticides. OP poisoning can occur in a variety of situations and can be accidental or suicidal. It is common in developing countries. The cholinergic syndrome is caused by acetylcholinesterase inhibition, and diagnosis is based on the clinical signs and symptoms as well as the measurement of inhibition of erythrocyte acetylcholinesterase and/or plasma cholinesterase activity. Antidotal treatment is with atropine, an enzyme reactivator such as pralidoxime and diazepam. Anticholinesterase OPs may produce effects other than the acute cholinergic syndrome, including the intermediate syndrome. Later effects may include organophosphorus-induced delayed neuropathy. Certain OPs are exploited for their anticholinesterase effects, including defoliants such as 'DEF', herbicides such as glyphosate, fire retardants and industrial intermediates. The toxicology of this group is heterogeneous and they may or may not possess anticholinesterase activity.
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PMID:Organophosphate poisoning. 841 73

For organophosphates or phosphonates to initiate delayed neuropathy two steps are necessary: (1) progressive covalent reaction with neuropathy target esterase (NTE) to produce a form of inhibited NTE which can be reactivated by incubation with aqueous potassium fluoride (KF) and (2) progressive "aging" of inhibited NTE to a form which can no longer be reactivated by KF. However, it has been shown recently that certain N-unsubstituted organophosphoro-monoamidates (analogues of methamidophos) cause delayed neuropathy even though the inhibited NTE appeared not to have aged (Johnson et al. (1991). Arch. Toxicol., 65, 618-624). In order to study the generality of this phenomenon, we have examined some N-substituted compounds. We report in vitro studies of inhibition and reactivation and aging of both NTE and acetylcholinesterase (AChE) prior to toxicological tests. All the compounds studied were less inhibitory to both NTE and AChE in concentrated rather than in dilute suspensions of EDTA-washed brain particles without added cofactors. There was an apparent disposal of up to 100 mumoles of test compound by particles from 95 mg hen brain, which is far greater than can be explained by covalent binding. The activity is distinct from calcium-dependent "A" esterase. Several N-alkyl phosphoromonoamidates were found to be potent and selective inhibitors of NTE: second-order rate constant for O-n-pentyl N-benzylphosphoramido-fluoridate (Cmpd 6) = 5.6 x 10(7) M-1 min-1 at 37 degrees, which is about 100x higher than for acetylcholinesterase (AChE). Inhibited NTE and AChE from several chiral phosphoromono-amidates did not reactivate spontaneously (21 hours at 37 degrees). Virtually 100% reactivation by KF of AChE inhibited by phosphoromonoamidates was achieved at all times tested. Acetylcholinesterase inhibited by 2,5-dichlorophenyl N,N'-di-n-butylphosphorodiamidate was 42-56% reactivated by incubation with KF (192 mM in pH 5.2 buffer for 30 minutes at 37 degrees). We believe this is the first report of reactivation of any enzyme after inhibition by a phosphorodiamidate. For NTE inhibited by tabun (O-ethyl N-dimethylphosphoroamidocyanidate), virtually complete and rapid aging (t1/2 = 5.5-8.4 minutes) was observed. Consistent but only partial reactivation by KF was achieved 2 or more hours after inhibition of NTE by Cmpd 6 or by its 2,6-difluoro-analogue (Cmpd 7). However, a small but significant aging (approximately 15-20% loss of reactivatability) was measured soon after a 1 minute inhibition by Cmpd 7, but no further change occurred in 21 hours.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interactions in vitro of some organophosphoramidates with neuropathy target esterase and acetylcholinesterase of hen brain. 849

The intermediate syndrome of organophosphate poisoning arises in the time interval between the acute cholinergic crisis of fasciculations and muscle weakness and the delayed neuropathy attributed to inhibition of the neuropathy target esterase. The conclusions derived from salient experimental and clinical studies are that intermediate syndrome relates to the severity of poisoning not the specific organophosphate and to prolonged inhibition of acetylcholinesterase activity of the erythrocytes, brain and muscle endplate with pre and post synaptic impairment of neuromuscular transmission. It is not related to delayed neuropathy.
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PMID:The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical observations. 852 92

A rodent model, the albino mouse, was used to investigate the in vitro and in vivo capacity of 2 organophosphate (OP) compounds, mipafox and ecothiopate, to inhibit enzymes considered to be involved in the mechanisms of OP toxicity. Mipafox and ecothiopate were chosen as model compounds because the former can produce a delayed neuropathy whereas the latter does not. Mipafox (110 mumol/kg, s.c.) inhibited brain acetylcholinesterase (AChE), neuropathy target esterase (NTE) and phenylvalerate hydrolases by 58, 64 and 65%, while diaphragm AChE and phenylvalerate hydrolases were inhibited by 66 and 80%, respectively. In contrast, ecothiopate (0.5 mumol/kg) had no effect on brain NTE or on brain or diaphragm phenylvalerate hydrolases. At the same time, diaphragm AChE was inhibited by 60% while brain AChE activity had increased by 15% of control. Mipafox was a potent inhibitor of AChE and NTE in vitro. Although ecothiopate was a highly potent anti-ChE in vitro, it had no inhibitory effect on NTE.
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PMID:Comparative studies of two organophosphorus compounds in the mouse. 852 98

Nine human acute poisonings due to intentional ingestion of organophosphorous pesticides are presented. Six of the victims died. Six patients were treated in the Intensive Care Unit (ICU) from 34 h to 45 d, while 3 were found dead by relatives. Two of the patients treated in the ICU fully recovered after 15 and 24 d while the third survivor developed delayed neuropathy. Organophosphate blood levels were determined on admission and during therapy, and in 1 case atropine and pralidoxime levels were also detected. Significant fluctuations of the plasma cholinesterase activity were observed during therapy. Postmortem analysis revealed higher levels of pesticides in organs (eg 23.1 micrograms fenthion/g kidney) and in fat (135.2 micrograms fenthion/g) than in blood (eg 4.8 micrograms fenthion/ml) and vitreous humor. Considerable pesticide was measured in testis (eg 5.8 micrograms fenthion/g, 0.8 micrograms methidathion/g) and uterus (170.5 micrograms malathion/g). Extracorporeal decontamination to enhance pesticide elimination is a therapeutic challenge.
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PMID:Experiences with acute organophosphate poisonings in Crete. 869 83

Organophosphorus pesticides (OPs) produce optico-autonomic peripheral neuropathy in human populations in districts where a large amount of pesticides have been used in agriculture. This report presents an epidemiological study that was performed in Kanagawa Prefecture. An autopsy case of a professional organophosphorus sprayer is reported. In addition, an experiment was performed to investigate a non-cholinergic chronic toxicity due to a certain OP. The epidemiological study revealed that 64 of 7,435 farmers showed vertical smooth pursuit defect of the eyes, impairments of modulation-transfer function (MTF) of the visual system and abnormal contraction dynamics of the pupil reaction to light stimuli, and a high residual level of OP was found in their blood. These abnormalities were reduced by treatment with antidotes such as atropine, prifinium bromide, and pralidoxime methiodide (PAM). The autopsy findings showed severe retinal degeneration with optic neuropathy and an obviously precocious progression of arteriosclerotic change in heart, brain, and retinal vessels. These findings can not be explained by cholinesterase inhibition alone. Experimental evidence showed that OP produced non-cholinergic impairment such as increase of Ca ions in retinal neurons. A generation of free radicals was noted in tissue-cultured retinal neurons. Blood selenium level was reduced by OP. These non-cholinergic actions may also explain the neural damage caused by long-standing low-dosage contact with OPs.
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PMID:[Ophthalmopathy due to environmental toxic substances especially intoxication by organophosphorus pesticides]. 871 73

The cholinergic toxicity of malathion is exacerbated by its isomerization product, isomalathion, which inhibits detoxifying carboxylesterases as well as target acetylcholinesterase (AChE). Previous work has shown that the four stereoisomers of isomalathion, (1R, 3R), (1R, 3S), (1S, 3R), and (1S, 3S), differ in their inhibitory potencies against either rat brain or electric eel AChE. The present study examined the relative inhibitory potencies of these stereoisomers and the totally racemic mixture (1RS, 3RS) against hen brain AChE and neurotoxic esterase (NTE) to provide new data on stereoselective inhibition of neurotoxicologically significant esterases and to assess the potential of these compounds to cause organophosphorus (OP) compound-induced delayed neurotoxicity (OPIDN). The order of potencies against hen brain AChE was (1R, 3R) > (1R, 3S) > (1RS, 3RS) > (1S, 3R) > (1S, 3S), with a 15-fold difference between the strongest (ki = 388 mM-1 min-1; 20 min I50 = 89.3 nM) and weakest (ki = 25.6 mM-1 min-1; 20 min I50 = 1354 nM) inhibitors. Both asymmetric centers contributed substantially and interdependently to inhibitory potency, but the effect of changing the configuration at phosphorus alone was greater than changing the configuration at carbon alone. None of the isomalathions was an effective inhibitor of hen brain NTE (extrapolated 20 min I50 values were 1.2 to 29 mM), yielding NTE/ AChE I50 ratios (neuropathy target ratios, NTRs) of 1.5 x 10(3) to 1.5 x 10(5). NTRs of this magnitude indicate that none of the isomalathions should initiate OPIDN, even after doses greatly exceeding the LD50. Therefore, reports of OPIDN or other neuropathic sequelae associated with malathion exposures in humans cannot be explained on the basis of NTE inhibition by contaminating isomalathions.
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PMID:Relative potencies of the four stereoisomers of isomalathion for inhibition of hen brain acetylcholinesterase and neurotoxic esterase in vitro. 880 51

1. Male albino mice were injected s.c. with an organophosphate (mipafox, ecothiopate or paraoxon). Treatments were either a single injection or multiple daily injections with lower doses for 5 or 8 days. At 3 h after injection the activity of brain and diaphragm acetylcholinesterase and of brain neuropathy target esterase (NTE) was measured. Also measured in the diaphragm at 3 h post dose was the duration of spontaneous miniature endplate potentials (eMEPPs), recorded extracellularly. 2. At 7 and 28 days after dosing action potentials and evoked endplate potentials, produced by stimulating the phrenic nerve at 30 Hz, were recorded in diaphragm muscle. The amplitudes, time-course and latencies of these potentials were measured and the variability of latencies (jitter) was calculated. 3. Single doses of mipafox (20 mg/kg), ecothiopate (0.192 mg/kg) or paraoxon (0.415 mg/kg) in the mouse produced ca. 70% inhibition of diaphragm acetylcholinesterase at 3 h after dosing. All three OPs produced a prolongation of the half-decay times of eMEPPs. 4. All three OPs in the above single doses produced increased muscle action potential (postjunctional) jitter but only mipafox produced an increase in endplate potential (prejunctional) jitter. Mipafox in a slightly reduced single dose (17.5 mg/kg) had no effect on prejunctional or postjunctional jitter. 5. Multiple dosing with mipafox (8 mg/kg daily for 5 days) increased both postjunctional and prejunctional jitter at both 7 and 28 days after the end of dosing. After multiple dosing with mipafox (5 mg/kg daily for 5 days) postjunctional (but not prejunctional) jitter was increased. Multiple doses of paraoxon (0.166 mg/kg daily for 5 days) or ecothiopate (0.76 mg/kg daily for 5 days) increased prejunctional and postjunctional jitter. 6. Depending on the dosing regime, all three OPs tested were capable of increasing both prejunctional and postjunctional jitter. Neither ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy. The prejunctional effects may be related to long-term inhibition of acetylcholinesterase and the triggering mechanism for increase in prejunctional jitter may involve a relationship between the inhibition of acetylcholinesterase and the time for which it is inhibited. The differences between the time-courses of increases in prejunctional and postjunctional jitter and the differential effects of the different multiple dosing regimes indicate that it is likely that the triggering relationship between enzyme inhibition and time is different for prejunctional and postjunctional effects.
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PMID:Effects of multiple doses of organophosphates on evoked potentials in mouse diaphragm. 905 11

Sensitivity of in-life parameters, biochemical endpoints, and susceptibility of various areas of the chicken nervous system to delayed neuropathy induced by tri-orthocresyl phosphate (TOCP) was assessed. Groups of hens were exposed to a single oral dose of TOCP of 0, 50, 200 or 500 mg/kg and the animals observed for 21 days. Perfusion fixed, paraffin embedded tissue sections were stained with Bodian's silver and Luxol blue and semi-thin epoxy sections with toluidine blue. Sciatic and tibial nerves, lumbosacral, midthoracic, and upper cervical spinal cord, medulla oblongata and cerebellum were examined using a semiquantitative scoring system. In pair-dosed hens inhibition of brain and spinal cord neurotoxic esterase (NTE) and cholinesterase and of plasma and erythrocyte cholinesterases was determined 24 hr and 48 hr after administration. At all dose levels NTE in brain and spinal cord and plasma cholinesterase was inhibited markedly. Quantitative inhibition of NTE was seen also in absence of neuropathy. Ataxia and body weight loss occurred in high-dose animals only, while dose-related neuropathy was seen in the distal tibial nerve, medulla oblongata and cerebellum. Ataxia was correlated best with neuropathy in peripheral nerves while degeneration of nerve fibers in the cerebellum, seen best in mid-longitudinal sections, was the most sensitive histological indicator of TOCP-induced delayed neuropathy. The particular susceptibility of spinocerebellar neurons was recognized long ago, but often has been neglected in delayed neurotoxicity studies and respective guidelines. Optimal sensitivity of toxicity tests is a prerequisite for risk assessment, can be cost efficient, and nowadays should be a main interest of animal welfare in order to reduce animals' suffering. Based on these data, determination of NTE inhibition together with histopathological examination of longitudinal sections of distal tibial nerves, mid-longitudinal sections of rostral cerebellum and cross sections of upper cervical spinal cord represents an optimally sensitive and cost efficient test requirement.
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PMID:Susceptibility of various areas of the nervous system of hens to TOCP-induced delayed neuropathy. 908 80


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