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)

Cholinesterase inhibitors induce changes in plasma hormones in the rat. Since these compounds induce hypothermia the question has been raised as to whether the endocrine responses are secondary to the fall in core temperature. The time course of the changes in temperature and plasma levels of corticosterone, growth hormone and prolactin have been examined following injection of diisopropylphosphofluoridate (DFP), soman or physostigmine. All three cholinesterase inhibitors caused an initial rise in corticosterone; DFP decreased growth hormone; physostigmine reduced prolactin. The time course of the hypothermia after DFP and soman did not correlate with that of the rise in corticosterone. The data do not suggest that the hormone changes are secondary to the temperature change.
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PMID:Relationship between the temperature and endocrine changes induced by cholinesterase inhibitors. 358 58

Recently it has been found that homogenates of Tetrahymena thermophila can hydrolyze the potent acetylcholinesterase inhibitors O,O-diisopropylphosphofluoridate (DFP) and O-1,2,2-trimethylpropylmethylphosphonofluoridate (soman). Upon purification of the DFP hydrolyzing activity 10-fold it had been noted that the soman hydrolyzing activity increased only 2-3 fold. Treatment with manganous ion and comparison of the soman and DFP hydrolysis rates of the homogenate indicated that a mixture of the squid-type and Mazur-type DFPases may be present. Subsequent purification of the enzymatic activities within the Tetrahymena-homogenate demonstrated that there are at least five functioning proteins of molecular weights 67,000 to 96,000. None are directly homologous to the DFPases found in hog kidney or squid. The enzymatic activities are designated DFPase-1 through DFPase-5. A hypothesis is presented that the functions of DFPases are in the normal metabolism of organophosphates naturally synthesized by T. thermophila.
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PMID:Discovery of multiple organofluorophosphate hydrolyzing activities in the protozoan Tetrahymena thermophila. 361 95

Male Sprague-Dawley rats daily treated with DFP (0.5 mg/kg/day, sc) exhibited signs of cholinergic toxicity such as tremors and muscle fasciculations between Days 3 and 5 comparable to those observed 15 min after a single acute signs-producing dose (1.5 mg/kg, sc). Further administration of DFP (0.5 mg/kg/day, sc) for 6-14 days led to tolerance development as evidenced by disappearance of the described toxicity signs. The protein synthesis inhibitor cycloheximide, when given in a nontoxic dose (0.5 mg/kg/day, sc) 1 hr before DFP (0.5 mg/kg/day, sc) administration, potentiated the DFP toxicity and rats died after the fifth injection. DFP-tolerant rats developed toxicity signs when subsequently treated with cycloheximide (0.5 mg/kg/day, sc) and DFP (0.5 mg/kg/day, sc). Each drug when given alone for 4 days caused 30-50% reduction of [14C]valine uptake in vivo into the free amino acids pool as well as its incorporation into proteins of brain and skeletal muscles. A combination of these drugs caused a significantly greater inhibitory effect on [14C]valine incorporation into proteins. Cycloheximide (0.5 mg/kg/day, sc) administered for 4 days did not significantly alter the levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), or carboxylesterase (CarbE) activities but potentiated the DFP-induced inhibition of the activities of these enzymes. It is concluded that the cycloheximide pretreatment potentiates DFP toxicity by a mechanism that is related to inhibition of the synthesis of proteins such as AChE, BuChE, and CarbE.
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PMID:Interaction of cycloheximide and diisopropylphosphorofluoridate (DFP) during subchronic administration in rat. 362 91

The effect of direct intrastriatal injection of three organophosphate cholinesterase inhibitors, DFP (diisopropylphosphorofluoridate), soman (pinacolyl methylphosphonofluoridate) and sarin (isopropyl methylphosphonofluoridate) has been studied on locomotor activity in the rat. The degree of ChE inhibition has been monitored in the striatum, as well as in surrounding brain areas and blood, in order to verify the selectivity of the treatment and rule out effects attributable to actions in these areas and/or the periphery. It has been determined that while enzyme activity is inhibited in the striatum by all three compounds, only DFP significantly reduces locomotor activity at doses that produce no other observable behavioral deficits, or significant leakage into the periphery. Behavioral recovery occurs before enzyme activity returns to control levels. Possible contributions of DFP's action on other neurotransmitters and on ChE in other brain areas to the inhibition of locomotor activity are discussed.
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PMID:Dissociation of locomotor depression and ChE activity after DFP, soman and sarin. 371 85

Larval acetylcholinesterase (acetylcholine acetylhydrolase) EC 3.1.3.7 of the trematode Schistosoma mansoni was characterized and purified by affinity chromatography. The enzyme was solubilized from sonicated cercarial tissue and showed a Km value of 1.83 mM and a Vmax value of 102 U/mg protein. It was characterized as a true AChE since it hydrolyses acetylthiocholine more than seven times faster than butyrylthiocholine, and since it was inhibited by high concentrations of substrate. The enzyme was purified by affinity chromatography on a Sepharose column of the inhibitor [N-(6-aminocaproyl-6-aminocaproyl)-m-aminophenyl] trimethyl ammonium. The purified enzyme eluted from the column by decamethonium bromide migrated as a single band of 500 kD on nondenaturing polyacrylamide gel electrophoresis (PAGE), whether stained for proteins or for enzymatic activity. Analysis by SDS-PAGE revealed two major polypeptide bands of 76 kD and 30 kD. By labeling the enzyme with 3H-DFP (di-isopropyl-fluorophosphate), the 30-kD polypeptide was shown to contain the active site of the enzyme, with an additional labeled band of 110 kD also being detected. On the basis of our data we suggest that the principal species of S. mansoni AChE is a tetramer of four subunit polypeptides each of MW ca. 110 kD which are not linked by disulfide bonds, and which are further cleaved into two fragments, one of MW 76,000 and one of MW 30,000, the latter bears the active site.
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PMID:Acetylcholinesterase of Schistosoma mansoni: purification and characterization. 372 10

Diisopropylphosphorofluoridate (DFP), an irreversible inhibitor of acetylcholinesterase (AChE) activity, when given as an acute dose (1.5 mg/kg, sc) caused fasciculations and induced necrosis in rat skeletal muscle fibers. No adaptation was seen to daily dosing of DFP (1.5 mg/kg, sc) since all rats died after the second or third injection. Daily dosing of DFP in a concentration (0.5 mg/kg, sc) that as a single dose did not cause symptoms, produced onset of fasciculations on the third day associated with a reduced number of muscle fiber lesions. Further administration of DFP (14 days) caused disappearance of fasciculations and loss of sensitivity to the necrotizing actions in all muscles tested (diaphragm, soleus, and extensor digitorum longus). Activity of all molecular forms of AChE was reduced to 20-24% of control when symptoms of cholinergic hyperactivity appeared. Continuous injections of DFP (0.5 mg/kg/day, sc) up to 14 days did not cause greater inhibition of AChE activity. Instead, recovery of enzyme activity, especially of the 4S and 10S forms, was seen. During this period choline acetyltransferase activity (ChAT) was increased in muscle (intramuscular nerves) while the postsynaptic nicotinic acetylcholine receptor (nAChR) density (Bmax) was decreased to 44% without a change in the affinity constant (KD). It is concluded that neuromuscular adaptation to DFP is caused by recovery of AChE activity due to de novo synthesis and reduction in the number of nAChR.
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PMID:Mechanisms of toxicity and tolerance to diisopropylphosphorofluoridate at the neuromuscular junction of the rat. 372 74

Crude homogenates of the ciliate protozoon, Tetrahymena thermophila, can hydrolyze the potent acetylcholinesterase inhibitors O,O-diisopropylphosphorofluoridate (DFP) and O-1,2,2-trimethylpropylmethylphosphonofluoride (soman). Characterization of the enzymatic activity of the homogenate has been performed. The DFPase operates over a pH range of 4 to 10 and an ionic range of 0-500 mM NaCl. Rate of reaction increases three- to four-fold from 25 degrees C to 40 degrees C and is still present at 55 degrees C. These results indicate that the enzymatic activity operates over a broad range of environmental conditions, making it an attractive material for use in the detoxification and detection of organofluorophosphates. DFPases may be important in the metabolism of naturally occurring organophosphates.
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PMID:Kinetics of the DFPase activity in Tetrahymena thermophila. 373 52

The effects of locally administered physostigmine and di-isopropylphosphorofluoridate (DFP) were compared on the secretory response of sweat glands to intradermally injected acetylcholine and carbachol in healthy male volunteers (physostigmine: six subjects; DFP: one subject). The response to acetylcholine reached its peak within 10 s of injection and then rapidly declined, whereas the response to carbachol increased steadily reaching a peak between 5 and 7 min after injection. The response to acetylcholine was potentiated in the presence of both physostigmine and DFP, whilst the response to carbachol was not significantly affected by either of these drugs. The difference in the time-course of responses to acetylcholine and carbachol may be attributed to differences in the susceptibility of the two drugs to metabolism by acetylcholinesterase; carbachol, unlike acetylcholine, being virtually immune to metabolism by this enzyme. It is concluded that the response to carbachol is mediated by a direct stimulatory action on post-synaptic muscarinic receptors rather than by activation of pre-synaptic nicotinic receptors leading to the release of endogenous acetylcholine.
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PMID:Effects of locally administered anticholinesterase agents on the secretory response of human eccrine sweat glands to acetylcholine and carbachol. 395 30

This report describes the distribution of histochemically identified 'non-specific' cholinesterase (ChE)-containing neurons in the dorsal thalamus of the rat. Juvenile or young adult Long-Evans or Sprague-Dawley rats were sacrificed by formalin perfusion. Some animals received systemic injections of 1.5-2.0 mg/kg DFP 4-24 h prior to sacrifice. Separate series of 50 micron frozen sections were processed for cholinesterase histochemistry using acetylthiocholine, butyrylthiocholine, or propionylthiocholine as substrates. Adjacent sections processed with each of the 3 substrates allowed comparison of the distributions of neurons containing the histochemical reaction products. Neurons containing moderate to high concentrations of ChE reaction product were found in 3 distinct regions of the dorsal thalamus. First, neurons staining intensely for ChE were found in a cluster that corresponds to the thalamic reuniens nucleus. Second, a cluster of neurons staining intensely for ChE was found in a region that included the lateral part of the central lateral nucleus and extended laterally into the ventral-lateral part of the lateral dorsal nucleus. Third, moderate ChE staining was observed in the neurons of the anterior dorsal nucleus. Of these regions, only the anterior dorsal nucleus shows moderate to high levels of acetylcholinesterase. The function of ChE in normal brain function is unknown. It is particularly interesting, however, that the thalamic nuclei containing ChE-positive neurons send thalamocortical projections to the medial limbic cortex, including cingulate, retrosplenial and subicular cortices.
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PMID:Distribution of 'non-specific' cholinesterase-containing neurons in the dorsal thalamus of the rat. 395 49

Tri-ortho-tolyl phosphate (TOTP), 360 mg/kg, po, and 0,0'-diisopropyl phosphorofluoridate (DFP), 1 mg/kg sc, were administered to adult White Leghorn chickens 24 hr after they were placed on diets containing 0 to 300 ppm corticosterone. Supplemented diets were continued until clinical signs and lesions of delayed neuropathy appeared. Although low concentrations (less than or equal to 50 ppm) of corticosterone had beneficial effects on TOTP-induced neuropathy, greater than or equal to 200 ppm exacerbated clinical signs in chickens given either TOTP or DFP. Neurotoxic esterase activities 24 hr after TOTP or DFP were less than 20% of values measured in chickens not given organophosphorous compounds. Chickens given 200 ppm corticosterone without TOTP or DFP had significantly elevated activity of plasma cholinesterase and significantly inhibited activity of liver carboxylesterase. Degenerating myelinated fibers were also evident in distal levels of the peripheral nerves of chickens given TOTP or DFP.
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PMID:Dose-related beneficial and adverse effects of dietary corticosterone on organophosphorus-induced delayed neuropathy in chickens. 396 13


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