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 identification of neuropathy target esterase (NTE) as the site for initiation of organophosphorus-induced delayed polyneuropathy (OPIDP) has led to informative acute and chronic neurotoxicity tests (adopted by OECD and EPA), to structure/activity and in vitro/in vivo predictions, and to a sound basis for extrapolations to man. Purification of the sodium dodecyl sulphate (SDS)-denatured 155-kDa sub-unit of NTE has enabled partial sequencing and molecular biological studies. A MAb to the chicken brain sub-unit and PAbs to synthetic peptides have been raised: preliminary experiments suggest that one is effective for immunohistochemistry of frozen tissue. cDNA libraries are being screened with synthetic oligonucleotides, polymerase chain reaction (PCR)-developed primers, and with Ab in order to obtain cloned NTE. Previous studies of NTE in vivo have not revealed its normal physiological function or the route from inhibition to degeneration of axons, but the current progress in molecular biology of NTE is applicable to study of the function of normal and organophosphorus (OP)-modified NTE in cultured neural cells.
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PMID:Neuropathy target esterase (NTE) and organophosphorus-induced delayed polyneuropathy (OPIDP): recent advances. 859 94

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

A method is presented for the isolation of a 155-kDa protein that possesses phenyl valerate hydrolysis activity in the presence of paraoxon but is inhibited by mipafox; the functional definition of neuropathy target esterase (neurotoxic esterase; NTE). Microsomes, isolated from 18-day-old chicken embryos were treated with phospholipase A2 to solubilize the NTE activity. The extract was then combined with polyoxyethylene W1 detergent and resolved by gel filtration chromatography to yield an active fraction with an approximate mass of 200 kDa. This fraction was further purified by preparative isoelectric focusing and native electrophoresis to yield two separate bands possessing NTE activity. The slower migrating band was highly enriched in a 155-kDa protein that was identified as a source of the NTE activity by affinity chromatography using 3-(9'-mercaptononylthio)-1,1,1-trifluoro-propan-2-one bound to Sepharose CL6B. This represents the first report of the isolation of NTE in its active form and aids in the confirmation of the 155-kDa protein as the most likely candidate for NTE.
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PMID:Identification and isolation of a 155-kDa protein with neuropathy target esterase activity. 881 9

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


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