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)

Single doses of certain organophosphates (OP), such as dibutyl-2,2-dichlorovinyl phosphate (DBDCVP) cause organophosphate-induced delayed polyneuropathy (OPIDP) in hens. Clinical effects correlate with inhibition of neuropathy target esterase (NTE) which is considered the target for this toxicity. Pre-treatment with non-neuropathic NTE inhibitors, such as phenylmethanesulfonyl fluoride (PMSF), protects from OPIDP. However, when given after OPs, these compounds promote OPIDP. Chicks are relatively resistant to OPIDP despite high NTE inhibition. It has also always been reported that rats represent a species which is resistant to OPIDP and that they might develop morphological but not clinical signs of OPIDP. We report here that clinical OPIDP can be produced in 3.5- and 6-month-old rats by DBDCVP (5 mg/kg s.c.) and that it correlates with high (> 90%) NTE inhibition. When PMSF (120 mg/kg s.c. x 2) was given after DBDCVP, OPIDP was promoted. Pretreatment with PMSF protected from OPIDP. We conclude that resistance to OPIDP in the rat is age-related, as it is in the hen.
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PMID:Clinical expression of organophosphate-induced delayed polyneuropathy in rats. 141 29

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 differential inhibition of the target esterases acetylcholinesterase (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SH-SY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced delayed neuropathy) and acutely neurotoxic OPs (i.e., those highly capable of inhibiting AChE). In these experiments, concentration-response data indicated that the capability to inhibit AChE was over 100x greater than the capability to inhibit NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaoxon) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than delayed, neurotoxic effects in vivo (e.g., chlorpyrifos-oxon, dichlorvos, and trichlorfon). In contrast, concentrations inhibiting AChE and NTE overlapped for neuropathy-causing OPs. For example, apparent IC50 values for NTE inhibition were less than 9.6-fold the apparent IC50 values for AChE inhibition when cells were exposed to the neuropathy-inducing OPs diisopropyl phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl saligenin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl-dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be considered useful in vitro models to distinguish esterase-inhibiting OP neurotoxicants.
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PMID:Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. 926 5

Neuropathy target esterase (neurotoxic esterase, NTE), a protein thought to be involved in the production of organophosphorus compound-induced delayed neurotoxicity (OPIDN), has been postulated to be a component of endogenous neuronal protein phosphorylation systems. The purpose of this work was to test this hypothesis as well as to investigate further the role of endogenous protein phosphorylation in toxic neuropathies. White Leghorn hens were dosed with the neuropathic compounds di-1-butyl-2,2-dichlorovinyl phosphate (dibutyl dichlorvos, DBDCV), tri-o-cresyl phosphate (TOCP), or acrylamide, and regions from brain were fractionated into axolemmal, synaptosomal, and microsomal preparations. Radiolabeling of NTE or endogenously phosphorylated proteins was carried out by incubation with [14C]-DFP or gamma-[32P]-ATP, respectively. Radiolabeled proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and visualized by autoradiography. Relative amounts of phosphoproteins were quantified by densitometry of the autoradiographs. Changes in endogenous phosphorylation of a protein exhibiting the characteristics of NTE were not observed in these experiments. However, levels of a [32P]-labeled 50-kDa brainstem axolemmal protein were decreased significantly on d 15, but not on d 1, 3, 7, or 10 after dosing with 2.8 mg/kg DBDCV. Clinical signs of ataxia and histopathological findings of axonal degeneration in the spinocerebellar tracts of the brainstem were evident on d 10-15, and hens were unable to perch on a horizontal wooden rod from d 12 after dosing with DBDCV. The decrease in the 50-kDa phosphoprotein was not observed on d 15 after the production of clinically evident neuropathy with either 14 daily doses of 50 mg/kg acrylamide or with a single dose of 500 mg/kg TOCP. These results suggest that NTE is not an endogenously phosphorylated protein under the conditions of these experiments. However, an effect on endogenous phosphorylation limited to a 50-kDa axolemmal protein was selectively produced by treatment with a neuropathic dose of DBDCV that was in evidence only after clinical signs and histopathological findings of axonopathy were apparent.
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PMID:Brainstem axolemmal protein phosphorylation in vitro in hens dosed with di-1-butyl-2,2-dichlorovinyl phosphate. 1070 44

Several esterase inhibitors, not capable of causing peripheral neuropathy by themselves, exacerbate organophosphate-induced delayed polyneuropathy (OPIDP) and other axonopathies. This effect was called promotion of axonopathies and it was found not to be associated with inhibition of neuropathy target esterase (NTE), the molecular target of OPIDP. The search for an esterase as the target of promotion has started long ago, when an eterogeneous group of esterases-hydrolysing phenyl valerate (PV) was identified in hen's sciatic nerve by means of selective inhibitors. Correlation studies in vivo indicated that the target of promotion may have been among the proteins present in the soluble fraction. When this soluble PV-esterase activity was separated on a Sephacryl-S-300 column, correlation was found between promotion and its inhibition in vivo. The electrophoretic analysis of this fraction indicated the presence of several proteins. Subsequent ion-exchange chromatography identified a protein of about 80 kDa molecular weight that was associated with PV-esterase activity. The inhibition of this activity did also correlate with promotion. The sequence of this protein identified it as ovotransferrin, but commercial preparations of ovotransferrin were found to lack PV-esterase activity. Binding experiments on this purified PV-activity and on commercial ovotransferrin using radiolabelled promoters were inconclusive. Titration of this PV-activity showed that about 20-30% of it is resistant to high concentrations of several inhibitors, suggesting heterogeneity of the fraction. In fact, bi-dimensional electrophoresis indicated the presence of several proteins. Finally, in vivo correlation experiments with p-toluensulfonyl fluoride showed that whereas this chemical does not promote OPIDP induced by dibutyl dichlorovinyl phosphate, it does inhibit about 80% of this PV-activity. In conclusion, available data indicate that the target of promotion is unlikely to be ovotransferrin. However, all promoters identified so far are esterase inhibitors suggesting that the target of promotion might be, indeed, a protein with esteratic activity.
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PMID:Peripheral nerve esterases and the promotion of organophosphate-induced neuropathy in hens. 1624 1