Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC) which are microsomal enzyme inducers, and methyl iodide (MeI), cobalt chloride (CoCl2) and tri-o-cresyl phosphate (TOCP) which are inhibitors of the enzymes glutathione transferase, cytochrome (cyt) P-450 and carboxylesterase, respectively, and then challenged with soman (i.p.) to know its LD50. Pretreatment with PB and MC increased and TOCP decreased, whereas MeI as well as CoCl2 did not alter the LD50 value of soman in rats. The 1/2 LD50 dose of soman did not affect the liver microsomal cyt P-450 level, but significantly lowered carboxylesterase (CaE) and cholinesterase (ChE) activities in liver microsomes and in blood plasma. Induction of plasma CaE was more important than microsomal CaE in PB-mediated protection against soman toxicity. Gel filtration of plasma into four protein fractions for their relative soman binding capacity showed that a high-molecular-weight protein fraction (180,000 daltons on SDS-PAGE) which had no CaE activity could bind soman 6 times more than the low-molecular-weight CaE-containing protein fraction (60,000 daltons on SDS-PAGE).
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PMID:Role of carboxylesterase in protection against soman toxicity. 276 74

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.
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PMID:Neuropathy target esterase in hens after sarin and soman. 276 93

Acetylcholinesterases, butyrylcholinesterases, and carboxylesterases appear to form kinetically a homologous enzyme series with respect to many substrates and inhibitors. The present paper evaluates the interaction of aprophen with acetylcholinesterases, butyrylcholinesterases, and carboxylesterases with respect to protecting the enzyme from organophosphate and carbamate inhibition, accelerating pralidoxime iodide (2-PAM) regeneration of the diisopropylphospho-enzyme, and comparing the inhibition and regeneration kinetics of a soluble mammalian acetylcholinesterase with that of bovine erythrocyte acetylcholinesterase. The irreversible inhibition kinetics of diisopropyl fluorophosphate (DFP) and eserine inhibition of fetal bovine serum acetylcholinesterase were typical of other acetylcholinesterases as indicated by the bimolecular inhibition rate constants, ki, of 7.7 +/- 1.3 X 10(4) M-1 min-1 and 2.9 +/- 1.7 X 10(6) M-1 min-1, respectively. Similarly, the bimolecular regeneration rate constant, kr, for 2-PAM regeneration of the diisopropylphospho-acetylcholinesterase was 14.7 M-1 min-1. The bimolecular rate constants, ki and kr, were not statistically perturbed when the reaction was monitored in the presence of aprophen with the fetal bovine serum acetylcholinesterase. Human serum butyrylcholinesterase was partially protected from DFP inhibition by aprophen with no detectable change in the bimolecular inhibition rate constant, ki. The regeneration of the diisopropylphospho-butyrylcholinesterase by 2-PAM was accelerated in the presence of aprophen by a factor of 2.7 over that of 2-PAM alone (8.4 +/- 2.2 M-1 min-1 to 23.1 +/- 2.6 M-1 min-1 respectively). Neither the inhibition (DFP) nor the regeneration (2-PAM) kinetics observed for the carboxylesterase was perturbed by the presence of aprophen.
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PMID:Kinetic investigations into the interactions of aprophen with cholinesterases and a carboxylesterase. 309 45

Sialate 9(4)-O-acetylesterases (EC 3.1.1.53) have been isolated from equine liver, bovine brain and influenza C virus. In this latter case, the esterase represents the receptor-destroying enzyme of the virus. The kinetic properties of these enzymes were determined with Neu5,9Ac2 and in part with 4-methylumbelliferyl acetate and Neu5,9Ac2-lactose. The Km values vary between 0.13 and 24 mM and the Vmax values from 0.55 to 11 U/mg of protein. The pH optima are in the range of 7.4-8.5, the molecular masses at 56,500 and 88,000 Da. In addition to a fast hydrolysis found for aromatic acetates, such as 4-methylumbelliferyl acetate or 4-nitrophenyl acetate, N-acetyl-9-O-acetylneuraminic acid is de-O-acetylated at the highest relative rate. Other substituents at the 9-position, such as lactoyl residues, or acetyl groups at other positions within the side chain are not hydrolyzed. Neu4,5Ac2, however, is a substrate for all 3 enzymes. The hydrolysis rates of this ester function, which renders sialic acids resistant to the action of sialidases, vary from 3 to 100% relative to Neu5,9Ac2. Whereas Neu5,9Ac2-lactose is hydrolyzed by the bovine and viral esterases, other O-acetylated sialic acids in glycoconjugates are only attacked by the enzyme from influenza C virus and not by that from bovine brain. The esterase from horse liver also releases 4-O-acetyl groups from equine submandibular gland mucin. By incubation with appropriate substrates and inhibition studies, carboxylesterase, amidase and choline esterase activities were excluded, as well as the cleavage of other acyls, e.g., butyryl groups. Thus, the enzymes investigated belong to the acetylesterases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sialate O-acetylesterases: key enzymes in sialic acid catabolism. 314 20

1. Rabbit serum was shown to contain two cholinesterases which hydrolysed acetylthiocholine and butyrylthiocholine and one cholinesterase which hydrolysed only butyrylthiocholine. 2. The three enzymes were identified by the kinetics of heat inactivation and kinetics of phosphorylation by the organophosphate VX. 3. Using selective inhibitors (iso-OMPA, eserine, BNPP and BW-284C51) it was shown that the hydrolysis of acetylthiocholine and butyrylthiocholine in untreated native serum had properties of acetylcholinesterase (EC 3.1.1.7), butyrylcholinesterase (EC 3.1.1.8) and also some properties of carboxylesterase (EC 3.1.1.1). 4. Separation of proteins (on PAA-gels) in untreated native serum gave four bands with acetylthiocholine and three with butyrylthiocholine. 5. The two cholinesterases hydrolysing both substrates corresponded to the slow moving bands on the gel. 6. The fastest moving band hydrolysing only butyrylthiocholine could be attributed to the cholinesterase least sensitive to VX.
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PMID:Cholinesterases in rabbit serum. 322 26

Recently, the question was raised as to why iso-OMPA, generally known as a selective irreversible inhibitor of butyrylcholinesterase (BuChE), potentiates soman toxicity in rats but not in mice. Mice are known to have higher carboxylesterase (CarbE) and lower BuChE activity in plasma than rat. It could be hypothesized that it is the iso-OMPA inhibition of plasma CarbE, and not of BuChE, which is responsible for potentiation of soman toxicity in iso-OMPA-pretreated rats. In order to test this hypothesis two doses of iso-OMPA were administered to rats prior to soman. The two doses were selected in such a way that both were high enough to inhibit more than 90% of plasma BuChE activity; plasma CarbE activity, however, was only slightly inhibited by the lower and substantially by the higher dose of iso-OMPA. Our results demonstrate that iso-OMPA-induced potentiation of soman toxicity correlates with the inhibition of CarbE and not with the inhibition of BuChE activity in rat plasma. Relative resistance of mice to iso-OMPA-induced potentiation of soman toxicity could therefore be explained by a higher proportion of CarbE activity remaining uninhibited after iso-OMPA pretreatment. By having their active centers unoccupied, CarbE molecules can bind soman and reduce its concentration in neuronal tissue and motor end-plates.
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PMID:Iso-OMPA-induced potentiation of soman toxicity in rat correlates with the inhibition of plasma carboxylesterases. 324 52

In an acute study, albino rats of both sexes were orally administered graded doses of Pirimiphosmethyl, and the statistically computed median lethal dose (LD-50) were 1861 and 1667 mg/kg body weight for male and female rats respectively. No treatment related changes were discernible with regard to food intake, growth, gross or histopathology of the organs. In a time-course study, the correlation between symptoms and degree of esterase inhibition was examined in rats administered the minimum lethal dose (MLD: 1000 mg/kg b.w.) of the insecticide. Time-course inhibition pattern of both cholinesterase (ChE) and non-specific carboxylesterase (NSE) activities in brain and plasma revealed maximum inhibition at 24 h post-treatment which correlated well with the intensity of symptoms. In a subacute study, groups of male rats were fed dietary Pirimiphos-methyl at 0, 10, 250, 500 and 1000 ppm for 28 days. Food consumption and growth rate were not affected throughout the experimental period. At necropsy after 28 days, no gross pathological changes were seen in any of the organs except a slight increase in liver weight at 1000 ppm. Though no statistical differences were observed in the levels of hepatic transaminases, a significant increase in serum transaminase was evident. Significant increase in the activities of hepatic ALP, beta-GLR and serum ALP were evident at 500 and 1000 ppm. Further, significant inhibition of plasma PChE was evident at 250, 500 and 1000 ppm while the degree of inhibition of brain AChE was significant only at the higher dosages. No histopathological alterations were observed in any of the organs.
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PMID:Toxicity of pirimiphos-methyl: I. The acute and subacute oral toxicity in albino rats. 338 33

Rats injected with a nonlethal acute dose (100 micrograms/kg, sc) of soman (pinacolyl methylphosphonofluoridate) exhibited signs of anticholinesterase toxicity beginning at 5-15 min with increasing severity and lasting for 4-6 hr. Generalized tremors and seizure activity indicated comparatively greater involvement of the central cholinergic system than peripheral neuromuscular effects. During peak toxicity, all the brain regions tested showed more than 95% inhibition of acetylcholinesterase (AChE) activity. The cortex area was maximally affected (99% inhibition). Among skeletal muscles, soleus AChE was most severely affected (94%) and extensor digitorum longus (EDL) the least (72%). Inhibition of EDL AChE occurred at a much slower rate than in brain and other muscles. Significant recovery of AChE activity was seen by 48-72 hr after soman treatment in both brain and skeletal muscles. By Day 7, recovery was virtually complete in skeletal muscles but not in brain, although significant recovery had occurred by this time. Muscle fiber necrosis developed within 6 hr in the soleus and diaphragm, while no necrotic fibers were found in the EDL. The 16 S AChE molecular form showed the fastest recovery of the AChE isozymes in all three muscles. Full recovery was seen after 7 days in soleus and was increased to greater than control activity in diaphragm and EDL. The inhibition pattern of butyrylcholinesterase (BuChE) activity was similar to that described for AChE activity, but the recovery was comparatively faster. Carboxylesterase activity in plasma was decreased to less than 10% of control within 1 hr and recovered to 53% of control within 24 hr. No significant inhibition was seen in hepatic carboxylesterase activity. It can be concluded that soman-induced acute toxicity is directly related to the rate and degree of AChE inhibition. A significant amount of soman binds to non-AChE enzymes with serine sites such as BuChE and carboxylesterases.
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PMID:Biochemical and histochemical alterations following acute soman intoxication in the rat. 356 14

The in vivo time course of cholinesterase inhibition was measured in brain, lung, spleen, hind limb skeletal muscle, diaphragm, intestine, kidney, heart, liver, and plasma of rats receiving 90 micrograms/kg soman, im. This dose of soman produced severe respiratory depression and transient hypertension, but no significant changes in the cardiac output or heart rate of anesthetized rats. The rate and maximal extent of in vivo cholinesterase inhibition by soman varied widely among the tissues. Although cardiac output was unchanged by soman administration, the blood flow in heart, brain, and lung (bronchial arterial flow and arteriovenous shunts) was increased, whereas blood flow in spleen, kidney, and skeletal muscle was decreased. The relative importance of tissue blood flow, tissue levels of cholinesterase and acetylcholinesterase, and tissue levels of soman-detoxifying enzymes (diisopropyl-fluorophosphatase and carboxylesterase) in determining the in vivo rate and maximal extent of cholinesterase inhibition was examined by multiple regression analysis. The best multiple regression model for the maximal extent of cholinesterase inhibition could explain only 63% of the observed variation. The best multiple regression model for the in vivo rate of cholinesterase inhibition contained three independent variables (blood flow, carboxylesterase, and cholinesterase) and could account for 94% of the observed variation. Of these three variables blood flow was the most important, accounting for 79% of the variation in the in vivo rate of cholinesterase inhibition. This suggests that it may be possible to use a flow-limited physiological pharmacokinetic model to describe the kinetics of in vivo cholinesterase inhibition by soman.
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PMID:The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats. 356 32

The interaction of dialkyl (alpha-carbometoxy-beta,beta,beta-trifluoroethyl) phosphates (RO)2P(O) . OCH(CF3)COOMe (R = Me, Et, Pr, Pri, Bu, Bui, Am, Hex) (I-VIII) with human erythrocyte acetylcholinesterase, horse serum butyrylcholinesterase, pig liver carboxylesterase was studied and acute toxicity in mice was estimated. Compounds (I)-(VIII) were not hydrolyzed by carboxylesterase, slowly and irreversibly inhibited acetylcholinesterase (kII = 10(2)-10(4) M-1 X min-1) and more efficiently inhibited butyrylcholinesterase and carboxylesterase (kII = 10(3)-10(7) M-1 X min-1). The structure--antienzymatic activity relationships were investigated. With increasing of hydrophobicity of alkoxy groups, antienzymatic activity to butyrylcholinesterase and carboxylesterase ("sites of loss") rises equally and more significantly, than antiacetylcholinesterase activity (delta lg kII 1.0 and 2.4 for R = CH3 and C5H11 resp.). Branching at the alpha-position of alkoxy groups leads to sharp reducing of acetylcholinesterase and butyrylcholinesterase inhibition constants, the carboxylesterase inhibition mechanism becoming reversible. Multiple regression analysis (the Kubinyi model) showed that influence of steric hindrances is revealed at the phosphorylation stage. It was found that phosphates (I)-(VIII) possess low acute toxicity in mice (900-2000 mg/kg). The toxicity of this homologous series appears to be independent of the hydrophobicity. Role of esterases in toxicological effect of compounds (I)-(VIII) is discussed.
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PMID:[Interaction of dialkyl(alpha-carbomethoxy-beta,beta,beta-trifluoro- ethyl) phosphates with mammalian esterases]. 356 18


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