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)

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

The interaction with neural neuropathy target esterase (NTE) and acetylcholinesterase (AChE) in vivo of methamidophos (O,S-dimethyl phosphorothioamidate), its resolved stereoisomers and five higher O-alkyl homologues has been examined along with the ability of these compounds to cause organophosphorus-induced delayed polyneuropathy (OPIDP) in adult hens. For the lower homologues AChE was more sensitive than NTE and it was impossible to achieve high inhibition of NTE in vivo without both prophylaxis and therapy against acute anticholinesterase effects; for the n-hexyl homologue high inhibition of NTE could be achieved without obvious anticholinesterase effects and spontaneous reactivation of inhibited AChE was seen as in vitro. The maximum tolerated dose of L(-) methamidophos or of the ethyl or iso-propyl homologues did not inhibit NTE more than 60%, and surviving birds did not develop OPIDP. The n-propyl, n-butyl and n-hexyl compounds caused typical OPIDP at doses causing a peak of 70-95% inhibition of NTE in brain, spinal cord and sciatic nerve soon after dosing. Racemic methamidophos caused unusually mild OPIDP associated with very high inhibition of NTE at doses estimated to be greater than 8 times the unprotected LD50 and the D-(+) isomer caused OPIDP at about 5-7 x LD50. Clinical effects correlated with histopathology in 19 out of 20 examined birds. In contrast to results of many previous studies with organophosphates and phosphonates, all these cases of OPIDP were associated with formation of inhibited NTE which could be reactivated ex vivo by treatment of autopsy tissue with KF solution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anomalous biochemical responses in tests of the delayed neuropathic potential of methamidophos (O,S-dimethyl phosphorothioamidate), its resolved isomers and of some higher O-alkyl homologues. 166 Jul 8

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60-90 mg/kg p.o., corresponding to 4-6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (greater than 70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5-6 days. High AChE inhibition (greater than 90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10-20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.
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PMID:Chlorpyrifos-induced delayed polyneuropathy. 171 37

Methamidophos causes acute cholinergic toxicity in several species, including man, and organophosphate-induced delayed polyneuropathy which has been reported in man but not in the hen. Acetylcholinesterase (AChE) and neuropathy target esterase (NTE) are thought to be the molecular targets of acute and delayed toxicity, respectively. The rate constants of inhibition (ka) and reactivation (k + 3) of human and hen brain AChE and NTE by methamidophos resolved optical isomers are here reported. NTE inhibition was progressive and irreversible. Human and hen NTE ka (M-1.m-1) for D-(+) methamidophos was 88 and 59, respectively, and for L-(-) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition. D-(+) methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 0.24 and 0.13; 10(3).k+3 (m-1) was 0.83 and 0.69, respectively. L-(-) Methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 5.7 and 2.8, whereas 10(3).k+3 (m-1) was 6.50 and 1.52, respectively. L-(-)-Inhibited AChE reactivated to about 60% for human and 30% for hen enzymes, respectively. D-(+)-Inhibited AChE reactivated to about 10-20% for both species. Maximal reactivation occurred within 4-6 h when a plateau was reached. The larger and faster reactivation of human AChE inhibited in vitro by L-(-) methamidophos suggests that a corresponding effect might be possible in vivo and therefore explain, in part, the relatively higher susceptibility of man to delayed polyneuropathy induced by racemic methamidophos which occurs, however, with doses always causing severe cholinergic toxicity.
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PMID:Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase. 178 39

To determine the active site residue, human milk bile-salt stimulated lipase (BSSL) was labelled with [3H]diisopropyl fluorophosphate (DFP). Partial sequence analysis of cyanogen bromide fragments (a total of 146 residues from 6 peptides) revealed 84% sequence identity with a putative rat lysophospholipase. Sequence analysis of a [3H]DFP-labelled peptide indicated that the active site serine was contained in the sequence Gly-Glu-Ser-Ala-Gly. In addition to similarity with rat lysophospholipase, this sequence showed homology with regions of human butyrylcholinesterase and electric ray acetylcholinesterase (68% identity). It is concluded that these proteins are members of a new supergene family.
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PMID:Human milk bile-salt stimulated lipase. Sequence similarity with rat lysophospholipase and homology with the active site region of cholinesterases. 199 11

A microtiter plate reader with an associated computer to average triplicate samples and subtract blanks was used for reading and calculating neurotoxic esterase (NTE, also known as neuropathy target esterase) activities in spinal cord regions of hens 4 hr after administration of diisopropylphosphorofluoridate (DFP, 0.5 mg/kg sc). Although NTE inhibition is an early indicator of organophosphorus ester-induced delayed neuropathy. DFP-induced inhibition was not greater in regions of the spinal cord where pathological changes are most notable. Acetylcholinesterase (AChE) activities and protein determinations were also done on these tissues using microassay methods. DFP-induced AChE inhibition was similar to NTE inhibition. In addition to the capability to be used for small regional esterase activity measurements, the microassay was advantageous because the number of samples incorporated into a single assay was increased and the time needed for the NTE assay was reduced by 50%. Total volume of incubate in each well was 0.3 ml; the incubate contained 1/20 quantities of sample and reagents necessary in more conventional assays. Validation of the microassay was performed by comparison with more conventional assays when measuring inhibition of NTE and AChE in brains of control and experimental hens of two different genetic strains (B13B13 and B21B21 white leghorns). Experimental birds were given DFP, 0.5 mg/kg sc, 24 hr before samples were collected. NTE activities in brains of control hens were similar using both types of NTE analytical procedures. Percentage inhibition of NTE caused by DFP was within 4% using both assay procedures in both strains of hens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A microassay method for neurotoxic esterase determinations. 201 36

The embryonic chick has long been a model for developmental biology and has often been recommended as a model system in developmental toxicology. More recently, several investigators have shown that the chick embryo also provides a good model for identifying the neurotoxic effects of environmental pollutants, especially cholinesterase-inhibiting pesticides. Although numerous studies detail the structural development of chick embryos, few describe embryonic levels of enzyme synthesis and their changes during development. In this study, the development of esterase activity in chick embryos was measured from day 9 of incubation until 46 days after hatching. Brain acetylcholinesterase (AChE) activity was detected on day 9 of incubation at a concentration of 0.364 mumoles/min/g tissue. An increase between AChE activity and age of the embryos was observed. In the liver, the nonspecific cholinesterases (ChE) and carboxylesterase activities during incubation were not different from activities after the chicks had hatched. Plasma ChE and carboxylesterase activities did not change with age after hatching. Brain neuropathy target esterase (NTE) activity was not detected on day 9 of incubation and was extremely low (6.12 nmoles/15 min/mg protein) the next day, but increased rapidly with increasing age. This study demonstrates that chick embryos have developed esterase activities in the brain and liver by day 10 of incubation and again confirms that the insensitivity of chick embryos and young chicks to organophosphorus ester-induced delayed neurotoxicity is not due to absence of NTE. In addition, the results provide baseline data for evaluating the response of embryonic and immature chicks to neurotoxicants and teratogens.
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PMID:Development of esterase activities in the chicken before and after hatching. 204 34

The in vitro and in vivo biochemical properties of O-hexyl, O-dichlorophenyl phosphoramidate (hexyl-DCP) as inhibitor of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) were studied, as well as their neurotoxic effects. The differences found were suggested to be due to biotransformation effects. In this work, the in vitro time-dependent degradation of hexyl-DCP by plasma, liver and brain homogenates of rat and hen at 37 degrees C at pH 7.4 are studied using 100 nM initial concentration. The loss of inhibitory potency against AChE was used as sensor of the biodegradation rate. An approximate estimation of the residual compound was made by comparison with an inhibition calibration curve. The rate of enzymatic degradation was corrected for the spontaneous hydrolysis. Rat tissues showed some higher activities (24, 17, 1 mU/g for plasma, liver, and brain, respectively) than hen (17, 6, 1 mU/g), with activities being highest for plasma and lowest for brain. Hexyl-DCP is a chiral compound. The loss of anti-AChE power could be due to degradation of only one of the two stereoisomers.
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PMID:Hen liver and plasma can metabolize hexyl-DCP phosphoramidate at a rate comparable to that of rat. 225 3

Reports that near-lethal doses of the pesticide methamidophos (O,S-dimethyl phosphoramidothioate) caused a delayed neurotoxicity (OPIDN) in humans and that another phosphoramidate, isofenphos, caused OPIDN in the hen at high doses, prompted a study of the abilities of acephate (O,S-dimethyl acetylphosphoramidothioate) to inhibit brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in vivo. Hens were treated orally with 5-700 mg/kg of acephate, or im with 50-200 micrograms/kg of diisopropyl-fluorophosphate (DFP, positive control) and sacrificed 24 hr later. Brain homogenates were assayed for AChE as an estimate of acute toxicity, for NTE to indicate acephate's potential to cause OPIDN, and for residues of acephate and its metabolite methamidophos. A range finding study confirmed the LD50 level for acephate was approximately 800 mg/kg. Regression analyses indicated an ID50 (a dose that inhibits 50% of activity) for acephate inhibition of AChE of 10 mg/kg and an extrapolated ID50 for inhibition of NTE of 1300 mg/kg, almost twice the LD50. In contrast, ID50 values for DFP were similar for AChE (146 micrograms/kg) and NTE (132 micrograms/kg). Brain methamidophos levels were 10 to 16 percent of the total acephate plus methamidophos brain concentration. The lower the dose of acephate, the higher was the relative percentage of methamidophos. The results show acephate is a more potent inhibitor of AChE than it is of NTE in hens and suggest it would be difficult to administer a single dose of acephate sufficient to cause OPIDN without killing the animal.
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PMID:Acetylcholinesterase and neuropathy target esterase in chickens treated with acephate. 228 53


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