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)

Rats have very high endogenous levels of serum carboxylesterase (CAE) compared to primates. This difference accounts for the lower sensitivity of rats to toxic organophosphates, which interact with CAE instead of the more critical acetylcholinesterase. Pretreatment of rats with CAE inhibitors potentiates the effects of organophosphates. In this study, the effects of three putative CAE inhibitors, 2-(o-Cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP), bis-p-nitrophenyl-phosphate (BNPP), and tetraisopropyl pyrophosphoramide (Iso-OMPA), on the hydrolysis of several commercially available substrates were determined. Respective kinetic constants Km and Vmax were derived and effects of inhibitors compared using saturating amounts of substrate. Data presented here indicate significant differences in substrate affinity (Km), reactivity (Vmax), as well as effects of inhibitors. CBDP inhibits hydrolysis of specific naphthyl and paranitrophenyl esters at relatively low concentrations (1-10 microM). In contrast, significantly higher concentrations (mM) of BNPP and Iso-OMPA were required for inhibition of serum esterase activity. Of the inhibitors tested, Iso-OMPA in general exhibited the smallest inhibitory effect on ester hydrolysis. Although inhibition of hydrolysis of specific paranitrophenyl and naphthyl esters occurred in the presence of similar amounts of CBDP, the degree of inhibition differed significantly (50-75% vs. greater than 90%, respectively). These data suggest that there exists in rat serum, a pool of naphthyl ester esterase activity that is very sensitive ex vivo (greater than 90% inhibition) to CBDP and may be very useful in validating a rodent model for soman toxicity.
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PMID:Effects of three reputed carboxylesterase inhibitors upon rat serum esterase activity. 205 4

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

We describe a quantitative slab gel electrophoresis procedure that allows quantitative determination of plasma levels of discrete cholinesterase isozymes. Using this method, the effects of haloperidol treatment on plasma cholinesterase isozyme levels were examined in normal rats. Eight isozymes were detected by enzymatic reaction with either of two substrates (alpha-naphthyl acetate, NA; acetylthiocholine iodide, AcTCh), and then quantified using densitometric scanning. With AcTCh substrate, the activities of two major isozymes (1 and 2) were found to be linear with increasing quantities of applied plasma. With NA as substrate, Iso-OMPA (a pseudocholinesterase inhibitor) inhibited activities of all isozymes, except isozymes 2 and 8. With either substrate, BW284C51 (acetylcholinesterase inhibitor) inhibited 100% and 13% of activity of isozymes 2 and 8, respectively, and with AcTCh substrate, 37% of isozyme 1. Based on the differential patterns of substrate specificity and action of inhibitors, and the reproducibility of patterns, we propose that these isozymes represent distinct molecular species. Short-term (14 days) and long-term (45 days) haloperidol treatment both resulted in altered levels of specific cholinesterase (ChE) isozymes. On the average, with AcTCh substrate, haloperidol treatment increased levels of isozymes 1 and 2 by 30% and 8%, respectively, after 14 days, and by 50% and 30%, respectively, after 45 days. Isozymes 3 through 8 showed minor changes. Plasma levels of isozymes 1 and 2 returned to baseline pretreatment values after a 40-day drug-free period. No significant change was observed after either short- or long-term treatment with clozapine, imipramine, or saline, or after an acute (less than 5 days) haloperidol treatment. No change was noted in RBC-ChE levels as function of treatment. These findings indicate that, in the rat, chronic haloperidol treatment results in differential changes in the plasma levels of discrete ChE isozymes. We have suggested that these changes reflect an alteration of central dopaminergic-cholinergic balance.
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PMID:Quantitative analyses of plasma cholinesterase isozymes in haloperidol-treated rats. 233 95

The role of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) in in regulating acetylcholine (ACh) lifetime was investigated by use of selective cholinesterase (ChE) inhibitors. Addition of 1 microM tetraisopropylpyrophosphoramide (iso-OMPA) led to a 98% inhibition of BuChE activity with little or no effect on AChE activity. This inhibition was accompanied by a 26% increase in the amplitude and a 43% prolongation in the half-relaxation time of contractions elicited by electric field stimulation (EFS). Coapplication of BW 284C51 (a selective AChE inhibitor) and 1 microM iso-OMPA resulted in increases of 2-fold in the amplitude and 10-fold in the half-relaxation time of EFS-induced contractions. These alterations were accompanied by small but sustained baseline contractures that were antagonized completely by incubation with exogenous BuChE (2.5 U/ml). The results suggest that BuChE serves to coregulate the lifetime of ACh in canine tracheal smooth muscle.
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PMID:Role of butyrylcholinesterase in canine tracheal smooth muscle function. 236 76

There are two tissue-fixed cholinesterases in dog pancreas: acetylcholinesterase and butyrylcholinesterase. In the present experiments, an organophosphate that only inhibits butyrylcholinesterase (isopropylpyrophosphoramide, or iso-OMPA) was compared with echothiophate and a nonorganophosphate compound, physostigmine. The latter two agents inhibit both cholinesterases. Fresh canine pancreas from anesthetized dogs was minced into fragments and suspended in Eagle's solution gassed with 100% O2. Amylase release was measured by the Phadebas method. In 2-h dose-response studies, there was a fivefold increase in sensitivity to acetylcholine when fragments were preincubated 1 h with iso-OMPA. There was a 1,000-fold increase in sensitivity when fragments were preincubated for 1 h in echothiophate. Basal amylase release in incubates with echothiophate were also increased. In dose-response studies with CCK-8, iso-OMPA was without effect, but echothiophate treatment resulted in a greater total response to CCK-8. There was a corresponding increase in basal output with echothiophate alone. Physostigmine also potentiates the response to CCK-8. Cumulative responses up to 3 h with half-maximal acetylcholine or half-maximal CCK-8 doses showed enhanced total output in fragments preincubated with echothiophate (p less than 0.05). The enhancement effect was atropine-sensitive to hexamethonium ganglionic blockade. In calcium-free medium, the enhancement with echothiophate was greatly reduced but still present. Inhibitors of both cholinesterases in the pancreas cause a greater total amylase release to sub-maximal doses of acetylcholine and CCK-8 than agents that only inhibit butyrylcholinesterase. Though our data do not provide direct proof, the results could be explained by a greater accumulation of endogenous acetylcholine when both cholinesterases are inhibited.
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PMID:Inhibition of acetyl- and butyrylcholinesterase and amylase release from canine pancreas. 247 12

Pretreatment of rats with the nonspecific esterase inhibitor iso-OMPA (1 mg/kg sc) 1 h prior to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate, 0.5 mg/kg sc) administration potentiated carbofuran toxicity by more than threefold. Neither iso-OMPA nor carbofuran in the given doses produced any gross toxic signs. Rats receiving combined treatment, however, showed severe hypercholinergic signs (salivation, tremors, muscle fasciculations, and convulsions) within 5-10 min following carbofuran administration, and the severity was comparatively greater than that observed with an acute dose of carbofuran (1.5 mg/kg sc). Rats pretreated with iso-OMPA (0.5 mg/kg) died within 10-15 min following the acute dose of carbofuran (1.5 mg/kg). Each drug when given alone (1.0 mg/kg iso-OMPA, 0.5 mg/kg carbofuran) caused a significant (p less than .01) inhibition of carboxylesterase (CarbE) activity in brain structures (cortex, stem, striatum, and hippocampus), skeletal muscle (hemidiaphragm), liver, and plasma, whereas acetylcholinesterase (AChE) activity remained significantly (p greater than .01) unchanged. The maximal CarbE inactivation in plasma (less than 14% remaining activity) following either drug indicated a tremendous nonspecific binding to non-AChE serine-containing enzymes. iso-OMPA pretreatment markedly potentiated carbofuran's anticholinesterase activity both in neuronal and in nonneuronal tissues. It can be concluded that iso-OMPA pretreatment potentiates carbofuran toxicity either by preventing nonspecific binding of carbofuran to CarbE and/or possibly by inhibiting its detoxification.
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PMID:Concerted role of carboxylesterases in the potentiation of carbofuran toxicity by iso-OMPA pretreatment. 270 39

Selective cholinesterase inhibitors such as BW284C51 and iso-OMPA showed that the plaques and tangles of Alzheimer's disease contain acetylcholinesterase and butyrylcholinesterase activity. In comparison to the cholinesterases of the normal brain, the plaque and tangle-bound cholinesterases in Alzheimer's disease display major shifts in optimum pH and inhibitor sensitivity.
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PMID:Special properties of cholinesterases in the cerebral cortex of Alzheimer's disease. 279 Apr 72

Neostigmine (5 X 10(-7) to 5 X 10(-6) M) and physostigmine (10(-5) M) each augment the responses of the rat anococcygeus muscle to field stimulation whereas iso-OMPA (5 X 10(-6) to 5 X 10(-4) M) or BW 62c47 (5 X 10(-7) to 5 X 10(-5) M) do not. At a concentration of 10(-5) M, neostigmine. BW 62c47 and iso-OMPA respectively produced a 48, 50 and 68% inhibition of cholinesterase activity in homogenates of anococcygeus muscle. The ED50 for cholinesterase inhibition by neostigmine (1.4 X 10(-5) M) is approximately 15 fold greater than the ED50 for the augmentation of the response to field stimulation (9.5 X 10(-7) M). It is concluded that the action of neostigmine in augmenting the response of the rat anococcygeus muscle to field stimulation is not a consequence of cholinesterase inhibition even though stimulation of muscarinic receptors is implicated.
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PMID:The effects of neostigmine on the response of the rat anococcygeus muscle to field stimulation are not a consequence of cholinesterase inhibition. 285 27

To obtain information about the evolution of acetylcholinesterase (AChE), we undertook a study of the enzyme from the skeletal muscle of the lamprey Petromyzon marinus, a primitive vertebrate. We found that the cholinesterase activity of lamprey muscle is due to AChE, not pseudocholinesterase; the enzyme was inhibited by 1,5-bis(4-allyldimethylammonium phenyl) pentane-3-one (BW284C51), but not by tetramonoisopropyl pyrophosphortetramide (iso-OMPA) or ethopropazine. Also, the enzyme had a high affinity for acetylthiocholine and was inhibited by high concentrations of substrate. A large fraction of the AChE was found to be glycoprotein, since it was precipitated by concanavalin A-agarose. Optimal extraction of AChE was obtained in a high-salt detergent-containing buffer; fractional amounts of enzyme were extracted in buffers lacking salt and/or detergent. These data suggest that globular and asymmetric forms of AChE are present. On sucrose gradients, enzyme that was extracted in high-salt detergent-containing buffer sedimented as a broad peak of activity corresponding to G4; additionally, there was usually a peak corresponding to A12. Sequential extraction of AChE in conjunction with velocity sedimentation resolved minor forms of AChE and revealed that the G1, G2, G4, A4, A8, and A12 forms of AChE could be obtained from the muscle. The identity of the forms was confirmed through high-salt precipitation and collagenase digestion. The asymmetric forms of AChE were precipitated in low ionic strength buffer, and their sedimentation coefficients were shifted to higher values by collagenase digestion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylcholinesterase from the skeletal muscle of the lamprey Petromyzon marinus exists in globular and asymmetric forms. 288 57

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


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