Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The organophosphates trichlorfon, dichlorvos, dimethoate, soman, triortho-cresyl phosphate (TOCP), and the diethoxy-analogue of trichlorfon (O,O-diethyl 2,2,2-trichloro-1-hydroxyethylphosphonate, ethyl-trichlorfon), were administered to guinea pigs between day 42 and 46 of gestation. When the offsprings were examined at birth, there was a severe reduction in brain weight in the case of trichlorfon and dichlorvos, but not after treatment with the other organophosphates. The reduction in weight was most pronounced for cerebellum, medulla oblongata, thalamus/hypothalamus and quadrigemina. The effect was less marked for cerebral cortex and hippocampus. Since soman, a potent anticholinesterase, and TOCP, an inhibitor of neuropathy target esterase, did not show any effects, this excludes that the brain hypoplasia can be caused by inhibition of these two enzymes. Further, the lack of effect with ethyl-trichlorfon has shed some light on the part of the trichlorfon molecule which could be involved in the formation of the hypoplasia. It is suggested that alkylation of DNA may be involved in the development of the lesion. The possible consequences for a teratogenic effect of trichlorfon and dichlorvos on humans are discussed.
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PMID:The effect of trichlorfon and other organophosphates on prenatal brain development in the guinea pig. 806 12

Organophosphorus compounds can cause two distinct toxic effects: acute, which are the consequence of acetylcholinesterase (AChE) inhibition and delayed neuropathy being inhibited by inhibition of neuropathy target esterase (NTE) with first signs (ataxia, paralysis) appearing 7-20 days after intoxication. The purpose of this study was to examine interaction of tabun with AChE and NTE and potential neuropathic effects of the compound in vivo. Tabun was more potent inhibitor reacting with more affinity with AChE than NTE of hen brain. The rate of aging of tabun-inhibited AChE was slow (t/2 = 50 hours) while it occurred very rapidly on tabun-inhibited NTE (t/2 = 6.5. min). Experiments in vivo have shown that even a high dose of tabun (12 mg/kg, 120 LD50), given with antidotes, which inhibited 67% of NTE activity did not initiate delayed neuropathic effects. It is concluded that there appears to be no risk for development of delayed neuropathy in tabun poisonings.
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PMID:[Anticholinesterase activity and delayed neurotoxic effects of tabun in hens]. 812 41

2-Substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides (2-substituted-BDPOs) are known to be potent neuropathy target esterase (NTE) inhibitors (I50s for the racemates of 0.2-3 nM) when the 2-substituents are n-alkyl (C5-C12), N-alkoxy (C7-C10), or p-n-alkylbenzyl (C3 and C4). The list of potent inhibitors (I50s < 3 nM) is expanded by the new n-alkylamino (C9) and n-alkylthio (C5, C7, and C9) analogs reported here. The optimal chain length of the 2-substituent is about 10 atoms in the alkylamino and alkylthio series as in our previous study on alkyl and alkoxy moieties. In contrast, an I50 of 60 nM is reported for o-methylphenoxy-BDPO, the neuropathic metabolite of tri-o-cresyl phosphate (TOCP). In addition to substituent effects, each of these compounds contains two enantiomers of unknown stereospecificity as NTE inhibitors. Separation by chiral HPLC with the CHIRALCEL OC column and hexane-2-propanol eluent gives individual enantiomers of > 98% e.e. and a stereospecificity for NTE inhibition depending on the type and chain length of the 2-substituent; e.g., the ratio for inhibitory potency of the individual enantiomers is 1.7-fold for nonylthio, 1255-fold for nonylamino, and 9-fold for the TOCP metabolite. In comparing enantiomeric pairs of BDPOs with alkyl, alkoxy, alkylamino, alkylthio, benzyl, p-butylbenzyl, o-methylphenoxy, or phenyl as the 2-substituent, the more retained enantiomer in HPLC is always the better NTE inhibitor (in a series of twenty-two pairs) and housefly toxicant (based on two pairs) than the less retained one.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuropathy target esterase inhibitors: enantiomeric separation and stereospecificity of 2-substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides. 815 29

Certain esterase inhibitors were found to exacerbate the clinical signs of polyneuropathy caused by various neurotoxic compounds and to delay the recovery from nerve crush. This phenomenon is referred to as promotion of axonopathies. The molecular target of promotion has not yet been identified. However, all known promoters are also inhibitors of neuropathy target esterase (NTE), the putative target of organophosphate neuropathy, but it has been shown that the target of promotion is unlikely to be NTE. Available data suggest that promoters might affect a target and a mechanism present in the nervous system that is not activated by axonal lesions. Promotion may be important to understand the physiological mechanism of nerve damage and repair. This finding also implies a changing perspective for the risk assessment of exposures to esterase inhibitors, some of which are used as pesticides and might be promoters.
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PMID:Promotion of peripheral axonopathies by certain esterase inhibitors. 819 2

Considerable evidence exists suggesting that the so-called neuropathy target esterase (NTE) is involved in the mechanisms responsible for organophosphorus-induced delayed polyneuropathy (OPIDP). Earlier studies in the adult hen, the habitually employed experimental model in OPIDP, have shown that most NTE activity in the brain is centered in particulate fractions, whereas approximately 50% of this activity in the sciatic nerve is encountered in soluble form, with the rest being particulate NTE. In the present work, we have studied the particulate and soluble fractional distribution of paraoxon-resistant phenylvalerate esterase activity (B activity), paraoxon- and mipafox-resistant phenylvalerate esterase activity (C activity), and NTE activity (B-C) according to ultracentrifugation criteria (100,000 g for 1 h). To this effect, two sensitive (adult hen and cat) and two scarcely sensitive (rat and chick) models were used. In all four experimental models, the distribution pattern was qualitatively similar: B activity and total NTE were much greater in brain (900-2,300 nmol/min/g of tissue) than in sciatic nerve (50-100 nmol/min/g of tissue). The proportion of soluble NTE in brain was very low (< 2%), whereas its presence in sciatic nerve was substantial (30-50%). The NTE/B ratio in brain was high for the particulate fraction (> 60%) and low in the soluble fraction (7-30%); in sciatic nerve the ratio was about 50% in both fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Soluble and particulate organophosphorus neuropathy target esterase in brain and sciatic nerve of the hen, cat, rat, and chick. 824 68

Incidence of numerous human poisonings by quinalphos (Ekalux, Bayrusil) in agricultural areas near Belgrade initiated this study on the ability of the compound to inhibit hen brain neuropathy target esterase, acetylcholinesterase and plasma butyrylcholinesterase in vivo. Hens were treated with a single oral dose ranging from 25 to 600 mg kg-1 quinalphos (LD50 = 72 mg kg-1) or 500 mg kg-1 triorthocresyl phosphate (positive control), sacrificed 24-96 h later for enzyme assays and monitored for 25 days for evaluation of walking impairments. High inhibition (> 80%) of both cholinesterases was obtained with 25 and 50 mg kg-1 quinalphos. Doses of 200 and 600 mg kg-1 of the agent inhibited up to 23 and 28% of hen brain neuropathy target esterase activity, respectively. Clinical signs of neuropathy were not seen. Quinalphos was slowly absorbed from the gastrointestinal tract, as indicated by the severity of the cholinergic symptoms and the inhibition of neuropathy target esterase, which reached its maximum 72 and 96 h after poisoning. The results suggest that quinalphos, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.
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PMID:Studies on the delayed neuropathic and anticholinesterase potential of quinalphos (diethyl 2-quinoxalyl phosphorothionate) in hens. 825 30

Biochemical responses after a single exposure to either a neuropathic or a nonneuropathic organophosphorus compound (OP) were compared using chick embryonic brain cell reaggregates. Ten-day-old chick embryo brains were dissociated and then reaggregated and maintained in a chemically defined, serum-free medium without antibiotics. Seven days later, these cultures were treated for 20 min with either neuropathic diisopropyl phosphorofluoridate (DFP, 10(-4) M) or nonneuropathic paraoxon (10(-6) M). Reaggregates were assayed for acetylcholinesterase (ACHE), neuropathy target esterase (NTE), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) activities for up to 32 days after exposure. These enzymes were examined due to inhibition of activity as a result of acute OP toxicity (ACHE) or delayed toxicity (NTE, CNP). DFP inhibited > 95% of NTE activity immediately after exposure. By Postexposure Day 2, NTE specific activity was 22% of untreated activity but was similar to the untreated group levels by Postexposure Day 7. Paraoxon exposure did not affect NTE activity. Both paraoxon and DFP inhibited > 99% of ACHE activity immediately after exposure. By Postexposure Day 2, ACHE specific activity in paraoxon-exposed cultures had recovered while ACHE remained 56% inhibited in DFP-exposed cultures. Both paraoxon- and DFP-exposed cultures recovered ACHE activity immediately following OP exposure if treated postexposure with an oxime reactivator, 2-pralidoxime. CNP specific activity was not affected by either paraoxon or DFP. These results demonstrated distinct differences in reaggregate NTE and ACHE activities after single exposure to neuropathic DFP and nonneuropathic paraoxon similar to those in avian in vivo assays.
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PMID:Avian embryonic brain reaggregate culture system. II. NTE activity discriminates between effects of a single neuropathic or nonneuropathic organophosphorus compound exposure. 829 Oct 56

A neuroblastoma cell line of human origin was used as an in vitro model system to examine early effects on inhibition of neuropathy target esterase (NTE, also known as neurotoxic esterase) in the presence of agents belonging to classes of chemicals previously demonstrated to modify organophosphorus-induced delayed neuropathy in hens. For this study, differentiated SY-5Y cells were treated for up to 10 min with mipafox, an organophosphorus compound, and NTE inhibition was determined when cells exposed to mipafox were also exposed to the carbamate, aldicarb, and to the calcium channel blocker, verapamil. Cells were exposed to aldicarb or verapamil 5 min before, at the same time, or 2 min after mipafox. Less NTE inhibition was observed when either aldicarb or verapamil was included in the incubation of SY-5Y cells with mipafox. Effects of aldicarb and verapamil on NTE inhibition in differentiated SY-5Y cells were similar to effects in chicken brain homogenates. These results indicate that NTE inhibition can be detected in neuroblastoma cells, that these cells respond in a manner similar to chicken brain, and that mipafox-induced inhibition of NTE can be decreased in the presence of aldicarb or verapamil.
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PMID:Modification of mipafox-induced inhibition of neuropathy target esterase in neuroblastoma cells of human origin. 833 99

Resolved isomers of O-n-hexyl-S-methylphosphorothioamidate (HXM) which had been synthesised by separate stereospecific routes were analysed by chiral glc: about 2-3% of R-(+) isomer was found in the S-(-) sample and accounted for nearly all the inhibitory power against neuropathy target esterase. Incubation of racemic HXM with rabbit serum led to slow but very specific disposal of R-(+) isomer to undetectable levels with very slight loss of S-(-): the rate of disposal was roughly estimated to be about 1% of the published rate of hydrolysis of paraoxon. Incubation with crystalline chymotrypsin caused a preferential but not totally selective disposal of S-(-) isomer.
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PMID:Stereo-specific degradation of the R-(+) isomer of O-n-hexyl-S-methylphosphorothioamidate catalysed by rabbit serum. 834 72

The kinetics of time- and concentration-dependent covalent organophosphorus inhibition of carboxylesterase isoenzymes (EC 3.1.1.1) and cholinesterase isoenzymes (EC 3.1.1.7 and EC 3.1.1.8) were investigated using a wide range of organophosphate inhibitor concentrations (10(-10)-10(-3) mol/l) and different inhibition times. Computerized analysis of inhibition curves by weighted non-linear least-squares curve fitting was compared to graphic analysis by iterative elimination of exponential functions. Possible experimental errors due to inhibitor saturation kinetics and enzymatic organophosphate hydrolysis were thoroughly investigated. In mammalian heart muscle, three different cholinesterase isoenzymes were identified. High sensitivity and specificity of the classic differential inhibition test for carboxylesterase activity of hen brain neuropathy target esterase (NTE) could be confirmed independently with both methods of inhibition curve analysis.
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PMID:Computerized analysis of covalent inhibition kinetics for identification of heart muscle cholinesterase and brain carboxylesterase isoenzymes. Design of differential inhibition assays. 834 80


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