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)

Some organophosphorus compounds (OP) induce a delayed polyneuropathy (OPIDP) which is initiated by the phosphorylation of the so-called neuropathy target esterase (NTE). In this work some aspects of hen sciatic nerve NTE are studied. The assay method is reported and modifications are discussed and a combined method proposed. Proximo-distal distribution showed a significant difference from proximal (100 +/- 10%) to distal (69 +/- 9%) fragments, in accordance with reported data. The time course of in vivo regeneration after a single TOCP dose (200 mg/kg, post oral) showed some differences when compared with hen brain NTE. Sciatic nerve NTE showed a delay of 2-3 days before regeneration but then regenerated faster (74% activity at day 7) than brain NTE (50% activity at day 7). A slower rate of regeneration of distal than proximal segments has been suggested to explain higher sensitivity of distal segments [3], however in this work no significant differences were observed in the rate of regeneration when comparing proximal and distal fragments.
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PMID:Sciatic nerve neuropathy target esterase. Methods of assay, proximo-distal distribution and regeneration. 337 20

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

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

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

Incorporating mechanistic information into the risk assessment process is necessary because proliferation of in vitro and in vivo tests of uncertain significance has led to the realisation that the quantity of toxicological information may undermine its own value. Default options in risk assessment to be used in the absence of mechanistic data are mainly derived from extrapolations. Examples from mechanistic studies on organophosphate-induced delayed polyneuropathy (OPIDP) will illustrate 3 main areas of extrapolation where mechanistic data might allow meaningful conclusions for risk assessment: (i) from animal to humans; (ii) from high to low levels of exposure; (iii) from disaggregated systems to complex systems. The continuing effort to understand the mechanisms of toxicity will reduce uncertainty in these and other areas of the extrapolation processes. It could also lead to better appreciation of the significance of biomarkers (such as lymphocyte neuropathy target esterase (NTE) for OPIDP) to be used in biomonitoring programs.
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PMID:Mechanisms of toxicity and risk assessment. 761 73

Methamidophos (O,S-dimethyl phosphorothioamidate) causes polyneuropathy in man and hens. However, experiments in the hen show that lower doses of methamidophos either protect from or promote the neuropathy caused by certain organophosphates. The initiation of neuropathy as well as protection from neuropathy are thought to be related to neuropathy target esterase (NTE), whereas promotion is likely to be due to interactions with another unknown target. Methamidophos is a racemate and we report studies with its resolved optical isomers, aimed at elucidating which isomer is responsible for the described effects. The time-course of acetylcholinesterase (AChE) and NTE activity in nervous tissues of hens after inhibition by single doses of either isomer showed that after D-(+) methamidophos (25 mg/kg PO) peak inhibition of both enzymes was achieved within 24 h (80-90%). However, after L-(-) methamidophos (15 mg/kg PO), peak inhibition (80-90%) was obtained within 24 h for AChE, whereas similar NTE inhibition (120 mg/kg PO) was observed only 4 days after dosing. The minimal neuropathic doses of D-(+) and L-(-) methamidophos were 60 and 120 mg/kg PO, respectively, and correlated with > 80% NTE inhibition in nervous tissues. OPIDP initiation by either isomer was slightly promoted by phenylmethanesulfonyl fluoride (120 mg/kg SC). D-(+) Methamidophos (25 mg/kg PO) partially protected from dibutyl dichlorovinyl-phosphate (DBDCVP) neuropathy (up to 0.8 mg/kg SC). This effect correlated with about 70% NTE inhibition. L-(-) Methamidophos (15 or 60 mg/kg PO) did not protect from DBDCVP neuropathy (0.2-0.8 mg/kg SC).
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PMID:Organophosphate polyneuropathy and neuropathy target esterase: studies with methamidophos and its resolved optical isomers. 765 38

Organophosphate-induced delayed polyneuropathy (OPIDP) is thought to be initiated by a variety of neuropathy target esterase (NTE) inhibitors. However, certain inhibitors such as phenylmethanesulfonyl fluoride, phenyl N-methyl N-benzyl carbamate, and phenyl di-n-pentyl phosphinate protect from OPIDP when given to hens before organophosphorus esters. They protect from neuropathy by preventing the binding of neuropathic inhibitors to NTE catalytic site. In contrast, when such NTE inhibitors are given afterward, the resulting clinical effect is more severe. This phenomenon was called promotion of OPIDP. Promotion has been tentatively explained by the interaction of promoters with a target other than the catalytic center of NTE. However, the doses of promoters which cause the effect have, so far, been found to always be inhibitory of NTE. We report that the phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S propyl ester (KBR-2822) given to hens at doses which did not inhibit NTE (2.5 mg/kg p.o.) promoted the neuropathies initiated by either dibutyl-2,2-dichlorovinyl phosphate (DBDCVP, 0.4 mg/kg s.c., 24 hr earlier) or diisopropyl phosphorofluoridate (DFP, 0.3 mg/kg sc or 0.5 mg/kg s.c., 24 hr earlier). When given alone, DBDCVP and DFP (0.5 mg/kg) caused mild OPIDP, whereas the lower dose of DFP did not cause clinical effects. Dose-response relationships with KBR-2822 indicated that clinical effects of the combined treatments are unlikely to be additive because the compound did not cause OPIDP up to the maximum tolerated dose (10 mg/kg p.o.). Promotion also occurred when KBR-2822 (2.5 mg/kg p.o.) was given before either DBDCVP (0.4 mg/kg s.c.) or DFP (0.3 mg/kg s.c.). NTE inhibitions in the nervous tissues caused by DBDCVP or DFP were not affected by pretreatment with KBR-2822, suggesting that the delivery of neuropathic. NTE inhibitors was not modified. We conclude that KBR-2822 promotes OPIDP initiated by either DBDCVP or DFP by affecting a target other than NTE catalytic site.
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PMID:The phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl ester exacerbates organophosphate polyneuropathy without inhibition of neuropathy target esterase. 797 86

The mechanism by which organophosphorus-induced delayed polyneuropathy is induced relates to the specific inhibition and subsequent modification ("aging") of a protein known as neuropathy target esterase (NTE), operatively defined as paraoxon-resistant and mipafox-sensitive phenyl valerate (PV) esterase activity. This protein has fundamentally been investigated in hen brain, the latter being the habitually employed OPIDP study model. In the present article, a partial characterization is made of the NTE and other related PV esterases in the bovine adrenal medulla and brain; NTE sensitivity to the neurotoxic organophosphorus compound mipafox is investigated, and its subcellular distribution is studied. The NTE activity of the adrenal medulla was found to be the highest of those among the tissues studied to date (5000 +/- 1400 mU/g tissue; +/- SD, n = 12). This activity represented 93% of the PV esterase activity resistant to 40 microM paraoxon in the particulate fraction of the adrenal medulla and approximately 50% of total PV esterase activity. In the bovine brain, these proportions were 72 and 26%, respectively, i.e., similar to those described in hen brain. The mipafox inhibition curve of PV esterase activity resistant to 40 microM paraoxon in the particulate fraction of the adrenal medulla suggests that NTE activity fundamentally comprises a mipafox-sensitive component with an I50 of 6.39 microM at 30 minutes, which is similar to the value reported in hen brain. NTE activity in the bovine adrenal medulla is almost exclusively limited to the particulate fraction, the microsomal fraction, plasma membrane, and chromaffin granule-enriched fractions being the highest in terms of specific activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Partial characterization of neuropathy target esterase and related phenyl valerate esterases from bovine adrenal medulla. 798 80

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


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