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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male rats administered with a single i.p. dose of 5 mg/kg methyl parathion, showed the toxic signs of hypercholinergic (anticholinesterase) activity with maximal severity, including muscle fasciculations and convulsions within 15 to 30 min, persisting for about 2 hr. The time course of acetylcholinesterase activity in discrete brain regions (cortex, stem, striatum and hippocampus), heart and hemidiaphragm, indicated its maximal depression during 30 to 60 min after administration of methyl parathion. At this time, a marked reduction in carboxylesterase activity was also evident both in neuronal and nonneuronal tissues, suggesting a tremendous binding to nonacetylcholinesterase serine sites. Pretreatment with memantine hydrochloride (18 mg/kg, i.p.) 30 min, and atropine sulfate (16 mg/kg, i.p.) 15 min before methyl parathion administration, completely prevented the expected toxic signs and significantly (P less than 0.01) attenuated the induced inhibition of acetylcholinesterase. When given therapeutically, this combined treatment completely reversed the clinical evidence of methyl parathion toxicity within 10 to 15 min and markedly reduced the acetylcholinesterase inactivation. These results suggest that memantine may counteract the acute methyl parathion toxicity by (a) protection of acetylcholinesterase from inhibition, (b) rapid reactivation of inhibited acetylcholinesterase and (c) rapid bioelimination of methyl parathion, in addition to cholinolytic effects of atropine sulfate.
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PMID:Methyl parathion acute toxicity: prophylaxis and therapy with memantine and atropine. 224 28

The toxicity of the organophosphorus poison soman (pinacolylmethylphosphonofluoridate) is attributable to its irreversible inhibition of the enzyme acetylcholinesterase. In addition, soman binds irreversibly to a number of noncholinesterase tissue binding sites which appear to be its major means of in vivo detoxification. This study was conducted to determine the hepatic subcellular localization of these sites. Subcellular fractions of liver from male Sprague-Dawley rats (200-250 g) were prepared by differential and isopycnic density gradient centrifugation. The binding of [14C]soman to these subcellular fractions was determined in the presence and absence of cresylbenzodioxaphosphorin oxide (CBDP), a compound that binds irreversibly to the noncholinesterase soman binding sites. Crude fractionation of liver homogenates into nuclear, mitochondrial, microsomal, and soluble fractions revealed that 78% of the total CBDP-sensitive binding activity was localized in the nuclear and microsomal fractions. Further purification of these fractions indicated that all of the homogenate binding activity could be accounted for in the purified microsomal fraction. When purified liver microsomes were solubilized and fractionated on linear sucrose gradients, 90% of the CBDP-sensitive soman binding activity cosedimented with carboxylesterase activity which suggests that these binding sites are carboxylesterase.
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PMID:Hepatic subcellular localization of cresylbenzodioxaphosphorin oxide (CBDP)-sensitive soman binding sites. 224 10

Liver and plasma acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase activities of the chick embryo and adult chickens were separated by sucrose density gradient sedimentation and further differentiated by their lectin affinities and organophosphate sensitivities. Changes in plasma cholinesterases during development indicated a characteristic shift in tetrameric (G4) isoforms from a slightly larger G4 AChE in the embryo to G4 BChE in the adult. These changes were not reflected in isoform patterns of liver homogenates, however. Interestingly, the time course of an increase in plasma BChE activity corresponded to the time course of a decrease in liver BChE activity, as if this enzyme was being mobilized and released. The distribution of liver esterases included both monomeric (G1) and G4 BChE and a large p-nitrophenylacetate (p-NPA) esterase activity that was separated into two main peaks by density gradient ultracentrifugation. The effects of organophosphate inhibitors indicated that the two liver p-NPA esterase activities may be regarded as carboxylesterases; however, these enzymes showed very different sensitivities to paraoxon and diisopropylfluorophosphate (DFP), with IC50 values differing by 3 and 4 orders of magnitude. Lectin affinity studies with multiple esterase forms suggested a heterogeneous group of glycoproteins that were packaged at different sites in the liver cell and were consistent with the presence of an intracellular precursor form to plasma BChE.
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PMID:Multiple molecular forms and lectin interactions of organophosphate-sensitive plasma and liver esterases during development of the chick. 224 23

Propoxur with a non-toxic dose (5 mg/kg) administered intraperitoneally (ip) in tetraisopropylpyrophosphoramide (iso-OMPA, 1 mg/kg) pretreated rats subcutaneously, sc) produced severe intoxication of anticholinesterase nature. The observed severity was comparable to that caused by an acute sublethal dose of propoxur (15 mg/kg) suggesting at least threefold potentiation of toxicity. Either drug given alone produced neither signs of toxicity nor alterations in acetylcholinesterase (AChE) activity, while carboxylesterase (CarbE) activity was markedly reduced indicating tremendous nonspecific binding. The administration of iso-OMPA followed by propoxur elicited inhibition of AChE to a critical level and produced severe intoxication. These results suggested that iso-OMPA induced potentiation of propoxur toxicity stemmed through irreversible inhibition of CarbE.
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PMID:Toxic interaction of tetraisopropylpyrophosphoramide and propoxur: some insights into the mechanisms. 225 6

Alterations in circulating esterases induced by dichlorvos and their reversibility were investigated in male buffalo calves. Changes in blood glucose and total plasma proteins were also monitored. Animals received 4 or 8 mg dichlorvos/kg/day po for 28 consecutive d. Dichlorvos caused dose- and time- dependent significant (P less than 0.01) inactivation of blood esterases. Maximal inhibition of plasma cholinesterase (87-94%) and serum carboxylesterase (51-67%) was observed on the 28th day. An increase in blood glucose and total plasma proteins occurred during the dosing period; these parameters returned to control values in surviving animals within 7 d after the final dose. Activities of esterases returned to 45-70% of normal the 14th d after cessation of dichlorvos dosing.
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PMID:The influence of repeated oral administration of dichlorvos on circulating esterases in buffalo calves (Bubalus bubalis). 226 71

Studies have been made of the effect of organophosphorus inhibitors on cholinesterase and carboxylesterase from various mammals (human erythrocytes, mouse brain, blood serum of mouse and rat, blood serum of horse) and arthropods (Calliphora vicina, Schizaphis graminum, Myzus persicae, Sitophilus oryzae, Pseudococcus maritimus, Tetranychus urticae). Organophosphorus inhibitors were presented by esters of vynylphosphoric acid containing normal and branched alkyls in the phosphoryl part of the molecule. The increase of the radical up to a propyl one increased the effect of organophosphorus inhibitors with respect to cholinesterase from the majority of the arthropods investigated. Organophosphorus compound with an isopropyl radical was found to be weaker for all the enzymes studied. Extremely high sensitivity of carboxylesterase from all arthropods to all organophosphorus inhibitors was noted; in some of the cases, anticarboxylesterase activity of all drugs was 2-3 orders higher than anticholinesterase one (P. maritimus, T. urticae). Regularities established for cholinesterase practically completely were confirmed on carboxylesterase. This finding evidently reveals similar structure of catalytic surface at the vicinity of esterase center in both enzymes.
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PMID:[A comparative study of the effect of vinyl phosphoric acid esters on cholinesterase and carboxylesterase activities in mammals and arthropods]. 236 Mar 79

Dichlorvos was applied as spray at 1 and 2% concentrations daily for a period of 28 and 21 consecutive days, respectively to buffalo calves. Animals sprayed with 1% dichlorvos displayed mild to moderate clinical signs of toxicosis during the 4th week of exposure. The higher concentration (2%) produced clinical signs of poisoning after 12-16 applications, and was lethal to one of three animals. Daily spraying of dichlorvos at both concentrations inactivated erythrocyte cholinesterase (ChE) (15-21%), plasma ChE (17-20%) and serum carboxylesterase (5-10%) within 3 days. The extent of inhibition of esterases was increased with repeated treatment and maximal inhibition of erythrocyte ChE (80-89%), plasma ChE (81-91%) and serum carboxylesterase (33-54%) with 1 and 2% concentrations was observed on the 28th and 21st day after start of application, respectively. In surviving animals, blood esterases remained inactivated to the extent of 14-65% on the 14th day after the termination of treatment. Dichlorvos at both concentrations significantly (P less than 0.01) elevated the serum levels of aspartate aminotransferase, alanine aminotransferase, acid phosphatase and alkaline phosphatase. The activities of these enzymes in surviving animals recovered to control values within 14 days after the final application of dichlorvos.
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PMID:Effects of repeated topical application of dichlorvos on blood enzymes and its toxicity in buffalo calves (Bubalus bubalis). 236 59

Carbaryl and aldicarb, two carbamate pesticides used extensively throughout the United States, are known to act as acetylcholinesterase inhibitors. We have demonstrated previously that exposure to carbaryl and aldicarb in young chicks caused persistent locomotion alterations with no correlation to esterase inhibition. In this study, we investigated the effects of these carbamates when injected in ovo to chick embryos, at two time periods (days 5 and 15) during incubation. Carbaryl dosed at 45 mg kg-1 egg weight was extremely toxic to the embryos on day 5 of incubation. Hatchability was reduced to 0% as compared to 80% when carbaryl was injected on day 15 of incubation. Aldicarb at 1.5 mg kg-1 egg weight had no major effect on hatchability when injected either on day 5 or day 15 of incubation (hatchability = 90 and 100%, respectively). Plasma, liver and brain esterases were measured in the chick at different time points during incubation and after hatching. Brain acetylcholinesterase (AChE) and liver cholinesterase (ChE) were inhibited significantly during incubation in embryos dosed on day 15 with both carbaryl and aldicarb. Liver carboxylesterase was inhibited significantly during incubation with only the carbaryl treatment. All esterase enzyme activities returned to normal after hatching. Plasma ChE and carboxylesterase levels were not affected with either carbaryl or aldicarb treatment from 8 until 47 days after hatching. Neither carbamate had any effect on brain neuropathy target esterase (NTE) activity either during incubation or after hatching. The locomotion of chicks was affected in both treatment groups until 47 days after hatching. This study indicates that carbaryl and aldicarb may cause long-term delayed alterations in the chicks.
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PMID:Effects of in ovo injection of carbamates on chick embryo hatchability, esterase enzyme activity and locomotion of chicks. 238 Apr 82

Species variation in oxime protection against soman was examined in mice and guinea pigs with the bis-pyridinium oxime HI-6. HI-6, an effective reactivator of soman-inhibited acetylcholinesterase, produced greater maximal protection against soman in mice than in guinea pigs, although there was no species difference in acetylcholinesterase reactivation. In mice the maximal therapeutic dose of HI-6 increased the LD50 of soman from 113 micrograms/kg in unprotected animals to 992 micrograms/kg in animals receiving 76.6 mg/kg of HI-6 and 11.2 mg/kg of atropine. In guinea pigs the maximal therapeutic dose of HI-6 increased the LD50 of soman from 28.2 micrograms/kg in unprotected animals to 179 micrograms/kg in animals receiving 136 mg/kg of HI-6 and 16 mg/kg of atropine. In animals whose carboxylesterase had been inhibited with 2 mg/kg of cresylbenzodioxaphosphorin oxide, the soman LD50 values in unprotected mice and guinea pigs were similar (10.2 vs. 12.2 micrograms/kg), as were the soman LD50 values in mice and guinea pigs protected with HI-6 and atropine (159 vs. 151 micrograms/kg). In cresylbenzodioxaphosphorin oxide-treated mice and guinea pigs the achievement of equal HI-6 protection against soman correlated with the ability of HI-6 to produce equal levels of reactivation of soman-inhibited acetylcholinesterase in both species. In animals whose carboxylesterase levels were different, the animals with higher carboxylesterase levels (i.e., mice) achieved higher levels of HI-6 protection against soman than did animals with lower levels of carboxylesterase (i.e, guinea pigs). This observation suggested that, in addition to its reactivation of soman-inhibited acetylcholinesterase, HI-6 produced an effect on carboxylesterase that increased its therapeutic effect in mice.
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PMID:Effect of endogenous carboxylesterase on HI-6 protection against soman toxicity. 238 81

Rodents are relatively insensitive to the neurotoxic effects of various organophosphorus compounds. The purpose of this investigation was to determine if differences in inactivation of CBDP could explain the strain differences in the sensitivity to neurotoxicity following administration of TOCP (tri-o-cresyl phosphate) observed by Carrington and Abou-Donia (1988). Serum carboxylesterase but not cholinesterase is an important detoxification route for organophosphates. Serum carboxylesterase and cholinesterase activity were significantly different (p less than 0.05) among the various strains of rats. The rank order of carboxylesterase activity was Sprague Dawley (6158 nmole/ml serum/min) greater than Long Evans (5589) greater than Fischer 344 (5010) whereas the rank order for cholinesterase activity was Fischer 344 greater than Sprague Dawley greater than Long Evans. TOCP is metabolized to the active neurotoxicant CBDP (2-/o-cresyl/4H:1:3:2-benzodioxaphosphorin-2-oxide). The ED50 for CBDP inhibition of serum carboxylesterase activity was found to vary considerably for the various strains of rats. The rank order of CBDP ED50 concentration in the various strains was Fischer 344 (437 microM) greater than Long Evans (339 microM) greater than Sprague Dawley (78 microM), indicating that there was a difference between the carboxylesterase of the various strains with regard to interaction with CBDP. It is suggested that the differences in the quantity of serum carboxylesterase combined with the differences in the interaction of the inhibitor with the enzyme(s) may be responsible for the strain differences observed by Carrington and Abou-Donia (1988).
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PMID:Serum carboxylesterase activity in various strains of rats: sensitivity to inhibition by CBDP (2-/o-cresyl/4H:1:3:2-benzodioxaphosphorin-2-oxide). 240 90


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