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)

The ability of a supralethal dose of chlorpyrifos to produce delayed neuropathy was examined using assessments of clinical signs, electromyography (EMG), motor nerve conduction velocity (MNCV), lymphocyte neuropathy target esterase activity (LNTE), and histologic changes in nervous system tissues. Cats were exposed to a single, im injection of corn oil (vehicle control), DFP (positive control) at 5.0 mg/kg, or chlorpyrifos at 300 mg/kg and observed for 60 days. Atropine and 2-PAM were administered to chlorpyrifos exposed cats one to two times a day for 14 to 24 days in response to the appearance of cholinergic signs. Anorectic cats during the acute toxicosis were force fed by hand and hydration was maintained by administering fluids sc. Onset of ataxia (mean +/- SD) for the positive control and chlorpyrifos exposed cats were 16.2 +/- 1.8 days (range of 14-19 days) and 19.0 +/- 1.4 days (range of 17-21 days), respectively. Functional deficits for both groups were confined to the hindlimbs and characterized by a crouched-waddling gait, hypermetria, and proprioceptive deficits. Maximal inhibition of LNTE activity was 96% at 24 hr postdosing in the positive control group and 46% at 7 days postdosing in the chlorpyrifos group. No EMG or MNCV abnormalities were detected in any of the treatment groups. Axonal degeneration was similar for the positive control and chlorpyrifos exposed cats. Ascending tracts of the cervical spinal cord and descending tracts of the thoracic and lumbar spinal cord were most severely affected and peripheral nerves were only mildly affected. The clinical and histologic effects produced indicate that chlorpyrifos can cause delayed neuropathy in the domestic cat. The moderate but prolonged inhibition of LNTE produced by chlorpyrifos is atypical of classic organophosphorus delayed neurotoxicants.
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PMID:Clinical, biochemical, electrophysiologic, and histologic assessment of chlorpyrifos induced delayed neuropathy in the cat. 128 30

The in vivo effect of a single dose of the neuropathic compound triorthocresyl-phosphate (TOCP) on phosphofructokinase (PFC, E.C. 2.7.1.11) and its relation with the initiation step (inhibition and aging of neuropathy target esterase, NTE) in the TOCP-induced delayed neuropathy have been studied. Hens were treated with a neurotoxic dose of TOCP (500 mg/kg, p.o.) and with a protective compound (Phenylmethanesulfonyl fluoride, PMSF, 30 mg/kg s.c.) in different combinations: TOCP, TOCP + PMSF, PMSF + TOCP and PMSF. PFK activity was determined in brain and sciatic nerve 1, 3, 7 and 15 days after treatment. PFK activity decreased in sciatic nerve 15 days after dosing with TOCP or TOCP + PMSF. When animals were dosed with the protective agent (PMSF) alone or before administering the neurotoxic compound, PFK activity was unaltered and clinical signs of neuropathy were absent. The data presented here suggest that phosphofructokinase is involved in the pathogenesis of the neuropathy induced by TOCP.
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PMID:Decrease of phosphofructokinase activity in relation to the pathogenesis of triorthocresyl-phosphate-induced delayed neuropathy. 130 29

It has been recently reported that phenylmethanesulfonyl fluoride (PMSF) when given to hens after a neuropathic organophosphate (OP) promotes organophosphate-induced delayed polyneuropathy (OPIDP). Chicks are resistant to OPIDP despite high inhibition/aging of neuropathy target esterase (NTE), the putative target of OPIDP initiation. However, when PMSF (300 mg/kg s.c.) is given to chicks after di-butyl 2,2-dichlorovinyl phosphate (DBDCVP, 1 or 5 mg/kg s.c.), OPIDP is promoted. Inhibition/aging of at least 30% of NTE was thought to be an essential prerequisite for promotion to be elicited in adult hens. However, we observed in hens that when NTE is maximally affected (greater than 90%) by phenyl N-methyl N-benzyl carbamate (40 mg/kg i.v.), a non-ageable inhibitor of NTE, and then PMSF is given (120 mg/kg/day s.c. x 3 days) clinical signs of neuropathy become evident. Methamidophos (50 mg/kg p.o. to hens), which produces in vivo a reactivatable form of inhibited NTE, was shown either to protect from or promote OPIDP caused by DBDCVP (0.45 mg/kg s.c.), depending on the sequence of dosing. Because very high doses of methamidophos cause OPIDP, we considered this effect to be a "self-promoted" OPIDP. We concluded that NTE inhibitors might have different intrinsic activities for producing OPIDP once NTE is affected. Aging might differentiate highly neuropathic OPs, like DBDCVP, from less neuropathic OPs, like methamidophos, or from the least neuropathic carbamates, which require promotion in order for neuropathy to be expressed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenylmethanesulfonyl fluoride elicits and intensifies the clinical expression of neuropathic insults. 131 17

Besides their well-known anticholinesterase action resulting in a typical acute cholinergic crisis, organophosphorus (OP) agents are capable of producing several subacute or chronic neurological syndromes. The acute over-stimulation at the neuromuscular junction results in muscle fiber necrosis. The significance of this OP-induced myopathy in human intoxication is unknown. Organophosphate-induced delayed neuropathy (OPIDN) arises 1-3 weeks after exposure to some OP compounds all capable of remarkably inhibiting a distinct esterase called neuropathy target esterase (NTE) during a critical time period. An experimental hen model has been designed to screen new OP compounds as to their delayed neurotoxic effects. The recently described intermediate syndrome emerges 1-4 days after an apparently well-treated cholinergic crisis. It main clinical features are sudden respiratory paralysis, cranial motor nerve palsies, and proximal limb muscle and neck flexor weakness. Whether or not this is a separate entity in OP agent toxicology remains to be seen. Further studies are required to further determine its clinical and paraclinical characteristics and the actual type of underlying neuromuscular dysfunction involved.
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PMID:Neurological aspects of organophosphate poisoning. 132 21

1 Interindividual variations in an unexposed population have been defined for five enzymes involved in organophosphate (OP) toxicity. The enzymes measured were: red blood cell acetylcholinesterase (AChE), lymphocyte neuropathy target esterase (NTE), serum cholinesterase (ChE), serum paraoxonase and serum arylesterase. 2 AChE and arylesterase were normally distributed in the population whilst the distribution of NTE, ChE and paraoxonase deviated significantly from normal. 3 Assay precision and intra-individual variability were measured for each of the enzymes; the effect on interindividual variation was assessed. 4 Variations in enzyme activities between individuals could have profound effects on susceptibility to OP toxicity. Prior determination of these enzymes may be predictive of susceptibility. 5 Lymphocyte NTE has some limitations as an indicator of exposure to neurotoxic OPs.
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PMID:Interindividual variations in enzymes controlling organophosphate toxicity in man. 134 16

The bases of using blood enzyme activity measurements [e.g. AChE, non-specific cholinesterase (BChE), carboxylesterase] as markers of organophosphate ester (OP) exposure are inhibition of activity by the binding of OPs to serine active sites in the enzymes, and the accessibility of the enzymes in RBCs and serum. The methods used to determine esterases in the blood of humans, experimental animals, and wildlife are outlined with emphasis on the acetylcholinesterase (AChE) of the red blood cell. Adaptations of an acetylthiocholine ester assay of Ellman et al. (1961) are common, but other colorimetric procedures, radiometric assays, and pH methods are also in use. Optimized, standardized methods are needed to assess exposures and provide a solid basis for risk assessment analyses. Useful adjuncts to ChE measurements are oxime reactivation tests and assay of neuropathy target esterase, an enzyme associated with organophosphate-induced delayed neuropathy. Determination of urinary metabolites compliments, but does not substitute for, the information obtained from blood ChE studies. Future assays are likely to involve antibodies to OP-protein complexes. Improvements in techniques permit the detection of small decreases in ChE activities. Whether or not such small decreases in ChE activities can, by themselves, constitute an adverse effect for input into risk assessment analyses is a controversial matter.
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PMID:Blood esterase determinations as markers of exposure. 141 Jun 89

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

The standard probes used earlier to study neuropathy target esterase (NTE) are N,N'-diisopropyl phosphorofluorodiamidate (mipafox), diisopropyl phosphorofluoridate (DFP), 2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin 2-oxide (2-CH3C6H4O-BDPO) (the neurotoxic metabolite of tri-o-cresyl phosphate), and dipentyl 2,2-dichlorovinyl phosphate (DDP) with I50s for hen brain enzyme of 7000, 700, 29, and 3 nM, respectively. NTE phosphorylated by DFP and DDP is proposed to undergo alkylation on aging, and this probably also occurs with 2-CH3C6H4O-BDPO. Optimized probes for NTE should meet the following specifications: highest potency achievable; rapid aging perhaps associated with alkylation; preferably a phosphonate so there are only two leaving groups. An attempt was made to achieve these goals in the 4H-1,3,2-benzodioxaphosphorin 2-oxide series by synthesis of 49 analogs systematically varied in the 2-alkyl, 2-alkoxy, or 2-(aryloxy) substituent. Special precautions are required in synthesis of BDPO derivatives because of their potential hazard on human exposure. Thirty of these compounds had NTE I50s lower than 3 nM. Representative high-potency NTE inhibitors in each series are [2-substituent,I50 (nM) for hen and human brain NTE, respectively]: octyl, 0.25 and 0.18; nonyloxy, 0.89 and 0.98; 4-propylphenoxy, 0.82 and 0.77. In comparing these compounds, although the octyl analog is the most potent in vitro NTE inhibitor, the propylphenoxy compound is the most effective in vivo NTE inhibitor and delayed neurotoxicant in hens. These benzodioxaphosphorins are improved probes for investigations on NTE phosphorylation and alkylation in relation to delayed neurotoxicity.
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PMID:Neuropathy target esterase inhibitors: 2-alkyl-, 2-alkoxy-, and 2-(aryloxy)-4H-1,3,2-benzodioxaphosphorin 2-oxides. 144 9

Diisopropyl phosphorofluoridate (DFP), mipafox, cresylsaligenyl phosphate, and phenylsaligenyl phosphate were applied to a 1.5-cm segment of the common trunk of the sciatic nerve in adult hens. At doses of 18-182 micrograms mipafox and 9-110 micrograms DFP, inhibition of neuropathy target esterase (NTE) for the treated segment was over 80%, whereas for the adjacent distal and proximal segments inhibition was under 40%, 15 min after application. NTE was not affected in the peripheral distal terminations arising from the common sciatic nerve (peroneal branches), contralateral sciatic nerve, brain, and spinal cord. A 24-hr study suggested a displacement of the activity-free region toward more distal segments of the nerve. All animals treated with 55 and 110 micrograms DFP or 110 micrograms mipafox lost a characteristic avian retraction reflex in the treated leg 9-15 days after dosing, suggesting peripheral neurological alterations. Only hens dosed at the maximum dose in both extremities presented alterations in motility (Grade 1 or 2 on a 0-8 scale), suggesting no significant central nervous system alterations. Electron microscopy of peroneal branches showed axon swelling and accumulation of smooth endoplasmic reticulum similar to animals dosed systemically (s.c.) with 1-2 mg/kg DFP. The branches also contained granular and electron-dense materials, as well as some intraaxonal and intramyelinic vacuolization. Clinical effects were not observed in animals protected with a 30 mg/kg (s.c.) dose of phenylmethanesulphonyl fluoride. It is concluded that the peripheral neurological effects of local dosing correlate with the specific modification of NTE in a segment of sciatic nerve and that the axon is a more likely target than the perikaryon or nerve terminal in the triggering mechanism of this axonopathy.
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PMID:Local application of neuropathic organophosphorus compounds to hen sciatic nerve: inhibition of neuropathy target esterase and peripheral neurological impairments. 147 Nov 54

The neurotoxic effects of single subcutaneous injections of 1000 mg triphenyl phosphite (TPP)/kg body weight were investigated in White Leghorn hens. At 7 days postexposure, birds began to show signs of mild to moderate ataxia that progressed to severe ataxia and paralysis at 21 days. Inhibition of whole brain neuropathy target esterase was 85% at 48 hr and 73% by 21 days postexposure. After postexposure periods of 7, 14, and 21 days, hens were killed and their brains and spinal cords were examined for degenerating axons and terminals using the Fink-Heimer silver impregnation method. A small amount of degeneration was noted at 7 days. By 21 days, dense degeneration was noted in the spinal gray matter and funiculi. Degeneration was also present in the granular cell layer of cerebellar folia I-VI and in nuclei and fiber tracts of the medulla. Moderate to dense degeneration was also seen in several forebrain and midbrain areas including the paleostriatum, ansa lenticularis, the dorso-intermediate thalamic nucleus, lateral spiriform, pedunculopontine tegmental, and lateral mesencephalic nuclei and in the deeper layers of the optic tectum. These results indicate that, in addition to affecting the spinal cord and brainstem, exposure to TPP also damages higher order centers responsible for processing and integrating sensorimotor, visual, and auditory information.
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PMID:Neuropathological effects of triphenyl phosphite on the central nervous system of the hen (Gallus domesticus). 160 Dec 12


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