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)

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

Organophosphorus esters have been used in the plastics industry as antioxidants and plasticizers, in agriculture as insecticides, and in the military as nerve agents. Some of these compounds have organophosphorus ester-induced delayed neurotoxicity (OPIDN) different from the acute toxicity caused by the acetylcholine esterase inhibiting activity. this review describes recent progress in studies on OPIDN and, discusses the future direction of studies. OPIDN is characterized by a more than 7 day incubation period, lower limb paralysis accompanied by axonal degeneration, and age- and species-specificity. Younger animals and rodents are not very sensitive to OPIDN. As well as fast recovery of inhibited neurotoxic esterase or neuropathy target esterase (NTE) in the sciatic nerve, detoxicating mechanisms including carboxylesterases are contributing to age- and species-specificity for OPIDN. Although, anterograde axonal transport does not seem to be affected by OPIDN, slow down of retrograde axonal transport was observed. Inhibition of NTE, and aging of inhibited NTE has been thought to be responsible for OPIDN, but there are some arguments against the role of NTE in OPIDN. Phosphorylation of cytoskeletal proteins by kinases such as calcium dependent-calmodulin kinase II and/or high affinity neurotoxic compound binding site(s) are possible candidates for the initiation of OPIDN. Triphenyl phophite (TPP), a compound commonly used in the plastics industry, has delayed neurotoxicity that is somewhat different from OPIDN. The onset of TPP-induced neuropathy is earlier than that of OPIDN, and rodents are sensitive to TPP. In addition to the axonal damage, cell damage is observed in TPP-induced neuropathy. Mitochondrial energy metabolism-related enzymes could be the target of this neuropathy. Future studies should be focused on the relation of OPIDN to the phosphorylation of cytoskeletal proteins and high affinity binding site(s), and on the development of rodent models. These studies would answer the questions related to OPIDN, and further contribute toward elucidating the pathogenesis of degenerative neuronal diseases.
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PMID:[A review of studies of the delayed neurotoxicity induced by organophosphorus esters]. 852 48

Single doses of triphenyl phosphite (TPP), a triester of trivalent phosphorus, cause ataxia and paralysis in hens. Characteristics of neurotoxicity were described as somewhat different from organophosphate induced delayed polyneuropathy (OPIDP), which is caused by triesters of pentavalent phosphorus. The onset of TPP neuropathy was reported to occur earlier than that of OPIDP (5-10 versus 7-14 days after dosing, respectively), and chromatolysis, neuronal necrosis and lesions in certain areas of the brain were found in TPP neuropathy only. Pretreatment with phenylmethanesulfonyl fluoride (PMSF) protects from OPIDP, but it either partially protected from effects of low doses or exacerbated those of higher doses of TPP. In order to account for these differences with OPIDP, it was suggested that TPP neuropathy results from the combination of two independent mechanisms of toxicity: typical OPIDP due to inhibition of neuropathy target esterase (NTE) plus a second neurotoxicity related with other target(s). We explored TPP neuropathy in the hen with attention to the phenomena of promotion and protection which are both caused by PMSF when given in combination with typical neuropathic OPs. When PMSF is given before neuropathic OPs it protects from OPIDP; when given afterwards it exaggerates OPIDP. The former effect is due to interactions with NTE, the latter to interactions with an unknown site. The time course of NTE reappearance after TPP (60 or 90 mg/kg i.v.) inhibition showed a longer half-life when compared to that after PMSF (30 mg/kg s.c.) (10-15 versus 4-6 days, respectively). The clinical signs of TPP neuropathy (60 or 90 mg/kg i.v.) were similar to those observed in OPIDP, appeared 7-12 days after treatment, correlated with more than 70% NTE inhibition/aging and were preceded by a reduction of retrograde axonal transport in sciatic nerve of hens. TPP (60 mg/kg i.v.) neuropathy was promoted by PMSF (120 mg/kg s.c.) given up to 12 days afterwards and was partially protected by PMSF (10-120 mg/kg s.c.) when given 24 h before TPP (60 or 90 mg/kg i.v.). The previously reported early onset of TPP neuropathy might be related to the higher dose used in those experiments and to the resulting more severe neuropathy. The lack of full protection might be explained by the slow kinetics of TPP, which would cause substantial NTE inhibition when PMSF effects on NTE had subsided. Since PMSF also affects the promotion site when given before initiation of neuropathy, the resulting neuropathy would then be due to both protection from and promotion of TPP effects by PMSF. No promotion by PMSF (120 mg/kg s.c.) was observed in TPP neuropathy (90 mg/kg i.v.) partially protected by PMSF (10-30 mg/kg s.c.). This might also be explained by the concurrent effects on NTE and on the promotion site obtained with PMSF pretreatment. We conclude that TPP neuropathy in the hen is likely to be the same as typical OPIDP. The unusual effects of combined treatment to hens with TPP and PMSF are explained by the prolonged pharmacokinetics of TPP and by the dual effect of PMSF i.e. protection from and promotion of OPIDP.
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PMID:Triphenylphosphite neuropathy in hens. 857 29

1. Available literature dealing with neuropsychopathological changes after exposure to organophosphate insecticides is reviewed. 2. Subacute neurological sequelae following acute organophosphate intoxication include the 'intermediate syndrome', probably a myopathy elicited by excess acetylcholine, and the 'organophosphate-induced delayed neuropathy' (OPIDN), which is caused by particularly neurotoxic organophosphates that inhibit neuropathy target esterase. 3. Long-term toxic effects affecting behaviour as well as mental and visual functions are occasionally observed after exposure to high doses of organophosphates with repeated acute, clinically significant intoxications. 4. The available data do not indicate that asymptomatic exposure to organophosphates is connected with an increasing risk of delayed or permanent neuropsychopathological effects.
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PMID:Neuropsychopathological changes by organophosphorus compounds--a review. 858 45

The relation between organophosphorus-induced delayed neuropathy (OPIDN) and brain neuropathy target esterase (NTE) inhibition is further examined in hens by structure-activity studies leading to the most potent in vitro NTE inhibitors known, which are then examined for their neuropathic effects in vivo in hens. The principal compounds studied are alkyl alkylphosphonofluoridates and dialkyl phosphorofluoridates. Potencies that exceed those of any previous inhibitors under the standard in vitro NTE assay condition are achieved with alkyl octylphosphonofluoridates (ethyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, and 3-iodopropyl), 2-iodoethyl hexylphosphonofluoridate, and dialkyl phosphorofluoridates [ethyl, nonyl; di(2-iodoethyl); di(3-iodopropyl); dipentyl]. The concentration for 50% NTE inhibition (I50) of these compounds is 0.04-0.14 nM. Thirty-eight less active analogs including aryl phosphonates and aryl phosphates give I50s of 0.27-4730 nM. For highest potency the summation of length of the alkyl and alkoxy groups on phosphorus should be 12-16 atoms (carbons, oxygens, and phosphorus) (a terminal iodo substituent in this relationship is equivalent to a propyl group). In general, the phosphonofluoridates and phosphorofluoridates are more active than analogs with leaving groups other than fluorine, i.e., phenoxy, 4-nitrophenoxy, 4-cyanophenoxy, 3,4-dichlorophenoxy, and 4H-1,3,2-benzodioxaphosphorin. Considering the exceptional potencies of ethyl and 2-iodoethyl octylphosphonofluoridates (I50s of 0.04 and 0.09 nM, respectively), it is not surprising that at ip doses of 10-30 mg/kg they inhibit brain NTE by 82-97% 48 h after treatment. However, unexpectedly, only the ethyl but not the 2-iodoethyl compound induces OPIDN, possibly associated with the greater ease of aging for NTE inhibited with the ethyl than the 2-iodoethyl compound (as observed in vitro both spontaneously and on induction by potassium fluoride). The high potency of ethyl octylphosphonofluoridate and several analogs as NTE inhibitors suggests that they are useful probes in determining the toxicological features of this secondary lesion for organophosphorus poisoning.
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PMID:Ethyl octylphosphonofluoridate and analogs: optimized inhibitors of neuropathy target esterase. 860 90

The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity.
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PMID:Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors. 868 3

Certain human lymphocytic enzymes, such as neuropathy target esterase (NTE), have become useful markers in clinical toxicology. NTE has been proposed as a predictive marker in organophosphate poisoning for the subsequent development of organophosphate-induced delayed neuropathy. We studied lymphocyte aryl hydrocarbon hydroxylases, and using a differential method based on that of NTE employing a phenyl-alkanoic substrate, developed an enzyme assay for use in toxic neuropathies. The assayed enzyme, which we refer to as neuropathy target hydroxylase (NTH), performed similarly to NTE in the evaluation of coherent clinical data obtained in patients with toxic neuropathies. This study indicates good correlation between the severity of clinical illness and abnormally low levels of NTH in neuropathies of varied etiology. A simplified protocol for NTH assay is presented.
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PMID:Lymphocyte esterases and hydroxylases in neurotoxicology. 872 18

Phenylmethanesulfonyl fluoride (PMSF) enhances the neuropathic response when given to hens after organophosphates causing delayed polyneuropathy. This study was undertaken to ascertain whether other sulfonyl fluorides promote diisopropyl fluorophosphate (DFP) neuropathy in hens and if they inhibit neuropathy target esterase (NTE), the target for organophosphate-induced delayed polyneuropathy. Among seven sulfonyl fluoride analogs of PMSF (alkyl-, and phenylsulfonyl fluorides), only n-butanesulfonyl fluoride was found to be an NTE inhibitor in vitro at a concentration (I50 = 60 microM) similar to that of PMSF, n-Butanesulfonyl fluoride (0.2 mmol.kg-1 sc to hens) caused both NTE inhibition in nervous tissues (> 80%) and promotion of neuropathy after DFP (0.003 mmol.kg-1 sc) similar to those observed after the same molar dose of PMSF. These results confirm that, so far, all known promoters of organophosphate polyneuropathy are also NTE inhibitors.
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PMID:Sulfonyl fluorides and the promotion of diisopropyl fluorophosphate neuropathy. 892 48

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

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


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