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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraoxon, an irreversible organophosphorus inhibitor of cholinesterase, produces a myopathy beginning at the neuromuscular junction in rat diaphragm muscles. Thirty minutes after paraoxon was injected i.p. (0.5 mg/kg), neuromuscular cholinesterase activity was reduced to 36% of control. The frequency of miniature end-plate potentials (MEPPs) in diaphragms from paraoxon-treated rats was 109/sec compared with 2.9/sec in saline-injected controls. The faster frequency was seen after paraoxon gradually declined to control rates within 6 hours after injection. The quantum content of end-plate potentials was reduced to 66% of that seen in saline controls. Spontaneous and impulse-related antidromic activity was observed along the phrenic nerve after paraoxon which also gradually diminished with time. When the phosphorylated acetylcholinesterase was reactivated with 10(-3) pyridine-2-aldoxime methiodide, MEPP frequency was reduced significantly and antidromic activity was abolished. Block of axonal excitability with 10(-6) M tetrodotoxin reduces the effects of paraoxon on MEPP frequency and antidromic activity, while acetylcholinesterase remains inhibited. In vitro perfusion with 6 times 10(-8) M paraoxon increases MEPP frequency and initiates antidromic activity. It is concluded that inhibition of neuromuscular cholinesterase by paraoxon leads to an alteration of transmitter release, and this may be associated with ultrastructural abnormalities observed at the motor endplate.
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PMID:Presynaptic effects of neuromuscular cholinesterase inhibition. 115 64

The binding of [3H] quinuclidinyl benzilate (QNB) to rat striatum membranes after diisopropylfluorophosphate (DFP) induced seizures was characterized. There was a 36% decrease in Kd and a 33% decrease in the number of muscarinic receptors. Paraoxon caused inhibition fo [3H] QNB binding to the striatal membranes of intact rats. It is possible that a direct action of DFP on the muscarinic receptor is not the cause of anti-cholinesterase-induced changes in [3H] QNB binding.
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PMID:[Effects of diisopropylfluorophosphate, paraoxon and dichlophos on [3H] quinuclidinyl benzylate binding to the rat striatum synaptic membranes]. 147 63

Cholinesterases of porcine left ventricular heart muscle were characterized with respect to substrate specificity and inhibition kinetics with organophosphorus inhibitors N,N'-di-isopropyl-phosphorodiamidic fluoride (Mipafox), di-isopropylphosphorofluoridate (DFP), and diethyl p-nitro-phenyl phosphate (Paraoxon). Total myocardial choline ester hydrolysing activity (234 nmol/min/g wet wt with 1.5 mM acetylthiocholine, ASCh; 216 nmol/min/g with 30 mM butyrylthiocholine, BSCh) was irreversibly and covalently inhibited by a wide range of inhibitor concentrations and, using weighted least-squares non-linear curve fitting, residual activities as determined with four different substrates in each case were fitted to a sum of up to four exponential functions. Quality of curve fitting as assessed by the sum of squares reached its optimum on the basis of a three component model, thus, indicating the presence of three different enzymes taking part in choline ester hydrolysis. Final classification of heart muscle cholinesterases was obtained according to both substrate hydrolysis patterns with ASCh, BSCh, acetyl-beta-methylthiocholine and propionylthiocholine, and second-order rate constants for the reaction with organophosphorus inhibitors Mipafox, DFP, and Paraoxon. One choline ester-hydrolysing enzyme was identified as acetylcholinesterase (EC 3.1.1.7), and one as butyrylcholinesterase (EC 3.1.1.8). The third enzyme with relative resistance to organophosphorus inhibition was classified as atypical cholinesterase.
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PMID:Cholinesterases of heart muscle. Characterization of multiple enzymes using kinetics of irreversible organophosphorus inhibition. 154 Feb 36

Paraoxon and chlorpyrifos-oxon, the active metabolites of the organophosphorus insecticides parathion and chlorpyrifos, respectively, are hydrolyzed by an "A"-esterase, paraoxonase, which is present in the sera of several mammalian species. In this study, we investigated whether levels of serum paraoxonase activity in laboratory animals can influence the in vivo toxicity of paraoxon and chlorpyrifos-oxon. Paraoxonase was found to be 7-fold higher in rabbit serum than in rat serum. The dose of paraoxon required to produce similar signs of toxicity and similar degrees of cholinesterase inhibition in rats and rabbits (0.5 and 2.0 mg/kg, respectively) differed by 4-fold. Paraoxonase was then purified from rabbit serum and 8.35 units was injected in the tail veins of rats, increasing the peak hydrolytic activity of rat serum by 9-fold toward paraoxon and by 50-fold toward chlorpyrifos-oxon. The increase in serum paraoxonase/chlorpyrifos-oxonase activity was long-lasting, with a 2- and 10-fold increase, respectively, still present after 24 hr. Thirty minutes following enzyme injection, rats were challenged with an acute dose of paraoxon or chlorpyrifos-oxon given by the intravenous, intraperitoneal, dermal, or oral route. Cholinesterase activities were measured in plasma, red blood cells, brain, and diaphragm after 4 hr. Rats pretreated with paraoxonase exhibited less inhibition of cholinesterase than vehicle-treated controls following identical doses of paraoxon, particularly when the organophosphate was given iv or dermally. A very high degree of protection, particularly toward brain and diaphragm cholinesterase, was provided by paraoxonase pretreatment in animals challenged with chlorpyrifos-oxon by all routes. These results indicate that levels of serum paraoxonase activity can affect the toxicity of paraoxon and chlorpyrifos-oxon.
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PMID:Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. 169 Apr 62

Paraoxon, 0,0-diethyl-0-p-nitrophenylphosphate is the highly toxic metabolite of parathion. The activity of paraoxonase, the enzyme which hydrolyses paraoxon in human serum shows a genetically influenced polymorphism with strong interethnic differences. The serum paraoxonase genotype has a significant influence on the paraoxon clearance and consequently on the toxic action of paraoxon and some related organophosphates and definitively protects the serum cholinesterase. Persons with low paraoxonase activity seem to be more endangered when handling parathion and related insecticides. More than 50% of all Europeans can be included in this group. The distribution of paraoxonase activity in human serum will be shown for samples which were collected from all over the world. As one moves from Europe in the direction of Africa and Asia the percentage of the low activity group decreases and was not even demonstrable in some tribes.
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PMID:Interethnic differences in the detoxification of organophosphates: the human serum paraoxonase polymorphism. 302 23

Rats treated intravenously with an organophosphorus anticholinesterase compound, paraoxon or soman, were sacrificed 2 to 131 min later, using 0.7 sec of focused microwave irradiation (25 kW at 915 MHz). Brain regional rates of glucose utilization during 3-min intervals were determined with labeled glucose and fluorodeoxyglucose as tracers. Levels of glucose, lactate, ATP, and creatine phosphate were assayed in the same samples. The two compounds differed markedly in their effects on brain metabolism. Paraoxon (0.8 LD50) depressed rates of glucose use in all brain regions, without causing consistent changes in brain metabolite levels. This depressant effect was most pronounced during the first 30 min after toxin exposure and had largely disappeared by 2 hr. Soman (0.8-0.95 LD50) was variable in its effects. Animals that showed seizure-like behavior had marked increases in glucose use in diencephalon and cerebrum but no changes in cerebellum or brain stem. Rapid rates of glucose use were associated with high levels of lactic acid and lower levels of creatine phosphate. In cerebrum, but not diencephalon, levels of ATP fell by as much as 50% in strongly affected animals by 30-130 min after soman. All of these effects were reversible with atropine. Soman-treated animals that did not have seizure-like activity did not exhibit these brain metabolic changes. These results and those of others show that cholinergic compounds vary greatly in their effects on brain glucose and energy metabolism. Although noncholinergic mechanisms are a possibility, the most parsimonious explanation for these findings is that cholinesterase inhibitors vary in their affinity for different central nervous system (CNS) acetylcholine receptor populations.
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PMID:Cerebral metabolic effects of organophosphorus anticholinesterase compounds. 350 39

1. Oxygen consumption in vitro and persistence in the general circulation of rabbit erythrocytes treated with the cholinesterase inhibitor paraoxon were determined.2. Paraoxon in vitro reduced oxygen consumption below a measureable level within 2 hours. By contrast, the metabolic inhibitor N-ethylmaleimide (NEM) produced complete inhibition within 15 minutes.3. Erythrocytes from rabbits orally dosed with parathion also exhibited marked depression of oxygen consumption.4. Glutathione (GSH) restored oxygen uptake to pretreatment levels within 15 min in erythrocytes previously inhibited with NEM or paraoxon.5. Erythrocytes treated with NEM were rapidly removed from the general circulation while paraoxon treated cells were removed at a rate comparable to untreated cells.
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PMID:Effect of paraoxon on erythrocyte metabolism as measured by oxygen uptake in vitro. 509 Nov 62

The esterase activity of guinea-pig serum was investigated. A 3-fold purification was achieved by removing the serum albumin by Blue Sepharose CL-6B affinity chromatography. The partially purified enzyme preparation had carboxylesterase and cholinesterase activities of 1.0 and 0.22 mumol of substrate/min per mg of protein respectively. The esterases were labelled with [3H]di-isopropyl phosphorofluoridate (DiPF) and separated electrophoretically on sodium dodecyl sulphate/polyacrylamide gels. Two main labelled bands were detected: band I had Mr 80 000 and bound 18-19 pmol of [3H]DiPF/mg of protein, and band II had Mr 58 000 and bound 7 pmol of [3H]DiPF/mg of protein. Bis-p-nitrophenyl phosphate (a selective inhibitor of carboxylesterase) inhibited most of the labelling of bands I and II. The residual labelling (8%) of band I but not band II (4%) was removed by preincubation of partially purified enzyme preparation with neostigmine (a selective inhibitor of cholinesterase). Paraoxon totally prevented the [3H]DiPF labelling of the partially purified enzyme preparation. Isoelectrofocusing of [3H]DiPF-labelled and uninhibited partially purified enzyme preparation revealed that there were at least two separate carboxylesterases, which had pI3.9 and pI6.2, a cholinesterase enzyme (pI4.3) and an unidentified protein that reacts with [3H]DiPF and has a pI5.0. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of these enzymes showed that the carboxylesterase enzymes at pI3.9 and pI6.2 corresponded to the 80 000-Mr subunit (band I) and 58 000-Mr subunit (band II). The cholinesterase enzyme was also composed of 80 000-Mr subunits (i.e. the residual labelling in band I after bis-p-nitrophenyl phosphate treatment). The unidentified protein at pI5.0 corresponded to the residual labelling in band II (Mr 58 000), which was insensitive to neostigmine and bis-p-nitrophenyl phosphate. These studies show that the carboxylesterase activity of guinea-pig serum is the result of at least two separate and distinct enzymes.
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PMID:The identification and characterization of two separate carboxylesterases in guinea-pig serum. 662 82

Cholinesterases in hen brain were characterized with respect to inhibition kinetics and substrate specificity. Three organophosphorus inhibitors were used: diethyl p-nitrophenyl phosphate (Paraoxon, E 600), di-isopropylphosphorofluoridate (DFP), and N,N'-di-isopropylphosphorodiamidic fluoride (Mipafox). The kinetics of irreversible cholinesterase inhibition were studied using two substrates, acetylthiocholine and butyrylthiocholine. The inhibition curves were analysed by the method of iterative elimination of exponential functions. Final classification of the different enzymes was done by combining two inhibitors in sequential inhibition expts. Six cholinesterases were shown to hydrolyse choline esters in hen brain, one was identified as acetylcholinesterase (EC 3.1.1.7) and one as cholinesterase (EC 3.1.1.8). Four enzymes can be classified as intermediate type cholinesterases according to their substrate specificity and to their inhibition constants. The possible role of different brain cholinesterases for the development of atypical symptoms following organophosphate intoxication is discussed.
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PMID:Brain cholinesterases. Differentiation of target enzymes for toxic organophosphorus compounds. 687 Sep 9

The effect of phosphotriesterase (PTE) on cholinesterase (ChE) activities was studied with exposures to different organophosphates in mice. Paraoxon (PO) (1.0 mg/kg, ip) almost totally inhibited serum ChE activity. This activity, however, recovered to the normal level within 24 hr. The PTE pretreatment (16.8 U/animal, 2.5 micrograms/10 g body wt, iv 10 min before the organophosphate) accelerated this reactivation. The same phenomenon was also seen in vitro. In vitro with human serum, there was only minimal reactivation of the inhibited ChE. PTE, however, reactivated it significantly. The PTE-pretreated mice (168 U/animal, 30 micrograms/10 g body wt, iv) tolerated even 50 mg/kg of PO without showing any remarkable signs of intoxication. In PTE-untreated animals, however, PO doses as low as 1.0 and 1.5 mg/kg caused severe signs of poisoning. PTE (16.8 U/animal, 4 micrograms/10 g body wt, iv) reduced the inhibition of brain and serum ChE activities after PO and diisopropyl fluorophosphate exposure. In sarin and soman intoxications, PTE decreased only slightly the inhibition of ChE activities. The results indicate that PTE pretreatment given iv prevents the inhibition of ChE activities after certain organophosphates and it also hastens the recovery of activities after PO poisoning.
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PMID:Phosphotriesterase--a promising candidate for use in detoxification of organophosphates. 786 9


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