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:3.1.1.5 (neuropathy target esterase)
1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simultaneous intoxication with hexacarbon solvents and organophosphorus compounds has been considered a possible critical factor in some occupational neuropathies and their interactions proved to cause potentiation effects in hens [1-3]. A high degree of inhibition of neuropathy target esterase (NTE) is needed to develop organophosphorus induced polyneuropathy (OPIDP). In this work, the inhibition of NTE, BuChE and AChE by TOCP on control and n-hexane pretreated (7-15 days, 300 mg/kg per day) hens is studied. Using a single TOCP dose of 200 mg/kg, n-hexane pretreated hens showed synergistic effects, but no significant differences were observed in the inhibition of cholinesterases and NTE in brain or spinal cord. With lower TOCP dose (20 mg/kg) statistically significant differences were observed, which were not drastic but could be important because they involved an increase of inhibition up to critical threshold values (from 40-50% to 60-70% inhibition). However, no clinical effects were observed in these animals. Possible mechanisms of neurotoxic interaction are discussed.
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PMID:Low non-neuropathic tri-o-cresyl phosphate (TOCP) doses inhibit neuropathy target esterase near the neuropathic threshold in n-hexane pretreated hens. 337 28

Phenyl di-n-pentylphosphinate is a reasonably stable easily synthesized inhibitor of neuropathy target esterase (NTE) with low anticholinesterase activity. Like phenylmethylsulphonyl fluoride it protects hens against neuropathic effects of compounds such as diisopropylphosphorofluoridate. At intervals up to 15 days after dosing hens (10 mg/kg s.c. to inhibit 90% NTE) assays were made of catalytically active and of phosphinylated NTE in autopsy tissue. The sum of these components was always within the range of catalytic activity in undosed controls. However, the half-life of reappearance of active NTE was 2.07 days +/- 0.13 (SD, n = 6) for brain and 3.62 days +/- 0.23 (SD, n = 6) for spinal cord--shorter than after dosing with phenylmethylsulphonyl fluoride. It is proposed that: (1) The physiological turnover mechanism cannot distinguish between catalytically active and di-n-pentylphosphinylated NTE although initiation of organophosphate-induced delayed polyneuropathy might involve recognition of aged di-alkyl-phosphorylated NTE as "foreign". (2) The short half-lives indicate a slow spontaneous dephosphinylation of inhibited NTE occurs in vivo as well as de novo synthesis. The difference in half-lives for brain and spinal cord NTE may be due to different rates of synthesis de novo or (more likely) to different rates of spontaneous reactivation of the inhibited NTE in the two tissues.
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PMID:Neuropathy target esterase: rates of turnover in vivo following covalent inhibition with phenyl di-n-pentylphosphinate. 341 44

Systemic injection of diisopropyl phosphorofluoridate (DFP; 1 mg/kg, sc) causes delayed neuropathy in hens. This effect is associated with a high level of organophosphorylation of neuropathy target esterase (NTE) followed by an intramolecular rearrangement called "aging." Phenylmethanesulfonyl fluoride (PMSF) also attacks the active center of NTE but "aging" cannot occur. This compound does not cause neuropathy and protects against a subsequent challenge systemic dose of DFP. Intraarterial injection of DFP (0.185 mg/kg) into only one leg of hens caused a high NTE inhibition (greater than 80%) in the sciatic nerve of the injected leg, but not in other parts of the nervous system (37% average). A unilateral neuropathy with typical histopathological lesions developed in the injected leg. PMSF (0.55 mg/kg) injected into each sciatic artery caused 47% inhibition of sciatic nerve NTE but only 17-22% inhibition of NTE elsewhere; it did not produce clinical or histopathological lesions. When these hens were challenged with DFP (1 mg/kg, sc), high inhibition of residual-free NTE (greater than 85%) occurred throughout the nervous system and clinical signs of a syndrome different from the classical delayed neuropathy developed: this spinal cord type of ataxia was associated with histopathological lesions in the spinal cord but not in peripheral nerve. PMSF (1 mg/kg) injected into only one sciatic artery caused selective protective inhibition of sciatic nerve NTE of that leg. After systemic challenge by DFP, clinical effects expressed were a combination of spinal cord ataxia plus unilateral peripheral neuropathy. The challenge dose of DFP (1 mg/kg, sc) was insufficient to produce clear histopathological lesions in unprotected peripheral nerves although spinal lesions were found in these hens. Thus clinical evaluation of the peripheral nervous system by means of walking tests and a simple test of "leg retraction" reflexes was more sensitive and specific in diagnosis of peripheral neuropathy than was the histopathology.
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PMID:Central-peripheral delayed neuropathy caused by diisopropyl phosphorofluoridate (DFP): segregation of peripheral nerve and spinal cord effects using biochemical, clinical, and morphological criteria. 356 33

The inhibitory power of organophosphorus compounds in vitro was compared against neurotoxic esterase (also known as neuropathy target esterase, NTE), acetylcholinesterase and carboxylesterase activities in brains from chickens, turkeys, quail and rats. Brains from the species most susceptible to clinical signs of organophosphorus-induced delayed neuropathy (chicken, turkey) contained more NTE than did rat and quail. Higher concentrations of organophosphorus compounds were required to inhibit rat NTE and quail acetylcholinesterase than were necessary for inhibition of these enzymes in chicken and turkey brains. Total carboxylesterase and acetylcholinesterase activities were less in rats than in the avian species.
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PMID:Comparative sensitivities of avian neural esterases to in vitro inhibition by organophosphorus compounds. 357 51

Cyclic phenyl saligenin phosphate (PSP) proved to be a potent delayed neurotoxin, eliciting clinical disease and lesions, and depressing neuropathy target esterase and plasma cholinesterase at much lower doses than the protoxicant tri-ortho-tolyl phosphate (TOTP). Using adult White Leghorn chickens, we noted qualitative similarities in clinical signs and peripheral nerve and spinal cord lesions elicited by PSP and the TOTP. Ataxia and weakness were prominent clinical effects. Lesions began as a distal axonopathy affecting larger myelinated fibers in spinal cord white matter and peripheral nerve. The latter were studied in detail. Major features of the lesion were intra-axonal collections of mitochondria, dense and lamellar bodies, and granular degeneration of neurofilaments. These led to Wallerian-like degeneration. Percentages of teased peripheral nerve fibers demonstrating such degeneration correlated with severity of clinical signs.
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PMID:Neuropathological effects of phenyl saligenin phosphate in chickens. 360 Dec 42

Organophosphate-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE), followed by an "aging" of the phosphorylated NTE. Prophylactic against OPIDP should thus be achieved by production of an inhibited but "nonaging" NTE. Resolved stereoisomers of ethyl phenylphosphonic acid esters produce two forms of inhibited NTE; in vitro one form ages rapidly and the other only negligibly. The present study examined the in vivo effects of two preparations of incompletely resolved isomers of EPN oxon (ethyl 4-nitrophenyl phenylphosphonate) and its thionate on adult hen brain and spinal cord NTE and the relationship of inhibition and aging to the development of OPIDP. Single doses of the L-(-)-isomers (Preparation A, 7:3 proportion of isomers, or Preparation B, 9:1) caused severe neuropathy after doses which produced 70% aged inhibited NTE and mild effects after 50-60%. Single doses of the D-(+)-isomers produced either equal amounts of aged and unaged inhibited NTE (Preparation A) or predominantly unaged (Preparation B): the amount of aged was never more than 50% and no clinical OPIDP occurred. Doses of D-(+) which produced 50% unaged inhibited NTE were protective: challenge with the highly neuropathic phenyl saligenin cyclic phosphate did not cause OPIDP. All effects are consistent with the two-stage initiation process which requires both inhibition of NTE and subsequent modification of the protein by an "aging" process. Previously reported neuropathic effects of D-(+)-EPN probably reflect a substantial proportion of L-(-)-isomer present in the test material. Neuropathic studies with chiral OP esters should consider the possibility of production of protective unaged inhibited NTE in test animals.
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PMID:The influence of chirality on the delayed neuropathic potential of some organophosphorus esters: neuropathic and prophylactic effects of stereoisomeric esters of ethyl phenylphosphonic acid (EPN oxon and EPN) correlate with quantities of aged and unaged neuropathy target esterase in vivo. 362 85

The target enzyme in organophosphorous-induced delayed neuropathy (OPIDN) has been designated neuropathy target esterase or neurotoxic esterase (NTE). NTE activity can be measured in blood lymphocytes and platelets, which could be of use as biomonitors in man at risk for the development of OPIDN. Separation of lymphocytes and platelets from whole blood, recovery, purity, storage and expression of data were examined. A substantial amount of the NTE activity of a human lymphocyte preparation made using Ficoll/Pacque was due to contamination by platelets; further purification was achieved by sucrose-gradient centrifugation. In an easily prepared sample of human platelets less than 10% of NTE was associated with contaminating white cells. We were unable to preserve NTE activity of platelets or lymphocytes at -80 degrees C either 'dry' or with added buffer and glycerol. In 68 male subjects, NTE activity in platelets averaged 8.36 +/- 1.54 nmol min-1 mg protein-1 and NTE activity in lymphocytes, obtained from blood after removal of platelets, 13.34 +/- 2.42 nmol min-1 mg protein-1. A good correlation was found between platelet and lymphocyte NTE activity. NTE activity in platelets may be a preferable method for measuring exposure to axonopathic organophosphorous compounds because of the ease and purity of separation. No correlation with other neuropathic risk factors such as age, smoking and alcohol intake was noted.
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PMID:Neuropathy target esterase in human lymphocytes and platelets. 395 22

Dilute solutions in cold dry ethyl acetate of 98-100% pure specimens of each of the four stereoisomers of soman were tested against enzymes in hen brain homogenate at 37 degrees and pH 8.0. Rate constants for progressive inhibition of acetylcholinesterase were 10(7)-10(8)/mole/min for both P(-) isomers and less than 10(5) for both P(+) isomers. All isomers inhibited neuropathy target esterase non-progressively to some degree. Rate constants for progressive inhibition of neuropathy target esterase were 2.7-3.8 X 10(5)/mole/min for C(-) P(+) and 2-6 X 10(4) for the others. Forced reactivation by KF was 90% initially and aging was slow in each case. Spontaneous reactivation of inhibited neuropathy target esterase was substantial during 18 hr for both P(-) isomers but not for P(+). By comparison of rate constants for the two enzymes we predict that pure P(+) isomers may cause delayed neuropathy in hens dosed at about unprotected LD50: prophylaxis and therapy against acute cholinergic effects would have to raise LD50 1000-fold before birds could tolerate potentially neuropathic doses of P(-) isomers.
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PMID:Interaction of the four stereoisomers of soman (pinacolyl methylphosphonofluoridate) with acetylcholinesterase and neuropathy target esterase of hen brain. 400 9

Measurement of neuropathy target esterase activity (NTE) in blood lymphocytes has been suggested as a possible biomonitor for organophosphate-induced delayed polyneuropathy. Human lymphocyte NTE was characterized in vitro according to the sensitivity to several organophosphate inhibitors, which was found similar to that of the nervous system enzyme. Methods for collection, storage, and processing of blood and the NTE assay are described (averaged coefficient of variation of the method is 8%). The mean (+/- SD) value of lymphocyte NTE activity in a caucasian population (108 healthy subjects) was 11.5 +/- 2.5 nMoles/min X mg of protein. No sex or age differences were detected. The averaged intraindividual coefficient of variation was 10.1%. These results suggest the feasibility of the test in clinical conditions, a sufficient reproducibility of the test, and a large interindividual variation. Appropriate baseline values are advisable when using the test to evaluate the effects of an occupational exposure to organophosphorus esters which may cause delayed polyneuropathy.
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PMID:Neuropathy target esterase in human lymphocytes. 402 82

Hens injected in one sciatic artery with diisopropylfluorophosphate (DFP) (0.184 mg/kg) developed monolateral ataxia on the injected side 10-12 days later. The inhibition of neuropathy target esterase (NTE) was 85% in the sciatic nerve of the injected leg and less than 60% in the contralateral sciatic nerve, in spinal cord and in brain. Other hens injected in the wing vein with the same dose of DFP showed low inhibition of NTE in the nervous system and did not develop delayed neuropathy. Hens injected in one sciatic artery with phenylmethanesulphonyl fluoride (PMSF) (1 mg/kg) and 24 hr later with high subcutaneous dose of DFP (1.1 mg/kg) developed monolateral ataxia 10-12 days later on the side not injected with PMSF. The level of NTE inhibition after PMSF was greater than 40% in the sciatic nerve on the injected side compared with less than 20% in other parts of the nervous system. The same dose of PMSF injected in the wing vein produced low NTE inhibition in the nervous system and failed to protect the animals from the same high systemic dose of DFP. We conclude that both toxic and protective effects of NTE inhibitors for delayed neuropathy are better related to the level of NTE inhibition in the peripheral nerve on the site of injection than to NTE inhibition in other parts of the nervous system. Furthermore we suggest that NTE inhibition should also be measured in the peripheral nerve in the standard toxicity testing for organophosphate-induced delayed neurotoxicity.
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PMID:Intra-arterial injection of diisopropylfluorophosphate or phenylmethanesulphonyl fluoride produces unilateral neuropathy or protection, respectively, in hens. 648 68


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