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)

Organophosphate (OP) poisoning produces various forms of acute, subacute, or delayed neurotoxicity. We investigated in vivo the relationship between clinical, histochemical and electromyographic (EMG) parameters in rats at various stages of poisoning by paraoxon or fenthion. Paraoxon is acutely toxic, whereas fenthion produces more sustained AChE inhibition. Fenthion has been involved in a subacute type of OP-related neurotoxicity in patients, the so-called intermediate syndrome. The animals underwent serial EMGs, with single and repetitive nerve stimulation, and concomitant contralateral muscle biopsies to determine the end-plate acetylcholinesterase (AChE) activity. Repetitive activity (RA) after single nerve stimulation and decrements on repetitive nerve stimulation (RNS) were the major EMG findings in either type of poisoning, occurring in the initial and later stages of the poisoning, respectively. RA was highly correlated to fasciculations in acute, but not in prolonged intoxication. Amplitude decrements provoked by RNS occurred only in weak rats with severe end-plate AChE inhibition. The smallest amplitude occurred either at the second response with gradual improvement in the subsequent responses (decrement-increment phenomenon), or the amplitude decrease progressed up to the last response (decrement phenomenon). The decrement-increment phenomenon preceded the decrement phenomenon and occurred at a slightly less severe degree of AChE inhibition. Various types of impairment of neuromuscular transmission coexist, probably to a different extent at distinct stages of anticholinesterase poisoning.
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PMID:Electromyography in relation to end-plate acetylcholinesterase in rats poisoned by different organophosphates. 799 Dec 22

A new conceptual approach was employed to antagonize organophosphorus intoxication by using resealed carrier erythrocytes containing a recombinant phosphotriesterase. This enzyme has been reported to hydrolyze many organophosphorus compounds, including paraoxon, a potent cholinesterase inhibitor. Paraoxon is rapidly hydrolyzed by this enzyme to p-nitrophenol and diethylphosphate. Incorporation of phosphotriesterase within resealed murine erythrocytes was accomplished by hypotonic dialysis. The properties of this enzyme within these resealed erythrocytes were investigated. Addition of paraoxon to reaction mixtures containing these resealed erythrocytes loaded with phosphotriesterase resulted in the rapid hydrolysis of paraoxon. Hydrolysis of paraoxon did not occur when these carrier erythrocytes contained no phosphotriesterase. These in vitro studies suggest that carrier erythrocytes may be developed as an approach for the prophylactic and therapeutic antagonism of organophosphorus intoxication.
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PMID:Encapsulation of phosphotriesterase within murine erythrocytes. 812 76

Biochemical responses after a single exposure to either a neuropathic or a nonneuropathic organophosphorus compound (OP) were compared using chick embryonic brain cell reaggregates. Ten-day-old chick embryo brains were dissociated and then reaggregated and maintained in a chemically defined, serum-free medium without antibiotics. Seven days later, these cultures were treated for 20 min with either neuropathic diisopropyl phosphorofluoridate (DFP, 10(-4) M) or nonneuropathic paraoxon (10(-6) M). Reaggregates were assayed for acetylcholinesterase (ACHE), neuropathy target esterase (NTE), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) activities for up to 32 days after exposure. These enzymes were examined due to inhibition of activity as a result of acute OP toxicity (ACHE) or delayed toxicity (NTE, CNP). DFP inhibited > 95% of NTE activity immediately after exposure. By Postexposure Day 2, NTE specific activity was 22% of untreated activity but was similar to the untreated group levels by Postexposure Day 7. Paraoxon exposure did not affect NTE activity. Both paraoxon and DFP inhibited > 99% of ACHE activity immediately after exposure. By Postexposure Day 2, ACHE specific activity in paraoxon-exposed cultures had recovered while ACHE remained 56% inhibited in DFP-exposed cultures. Both paraoxon- and DFP-exposed cultures recovered ACHE activity immediately following OP exposure if treated postexposure with an oxime reactivator, 2-pralidoxime. CNP specific activity was not affected by either paraoxon or DFP. These results demonstrated distinct differences in reaggregate NTE and ACHE activities after single exposure to neuropathic DFP and nonneuropathic paraoxon similar to those in avian in vivo assays.
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PMID:Avian embryonic brain reaggregate culture system. II. NTE activity discriminates between effects of a single neuropathic or nonneuropathic organophosphorus compound exposure. 829 Oct 56

Accuracy in measurement of plasma free fatty acids (FFA), and therefore prevention of the in vitro lipolysis, is a crucial step to understand the physiologic role of plasma FFA and their relationships in the pathogenesis of important metabolic disorders such as central obesity, insulin resistance, and diabetes mellitus. As lipoprotein triglyceride-fatty acids are elevated in these states, in vitro lipolysis of triglycerides may artifactually increase FFA. Plasma FFA were measured in subjects before and after heparin administration, under different experimental conditions affecting the in vitro activity of lipoprotein lipase (LPL) and hepatic lipase (HL). Paraoxon, a cholinesterase inhibitor neurotoxin known to block plasma lipolytic activity, and preextraction timing and temperature of collection were tested. Paraoxon was required to prevent triglyceride hydrolysis in: a) preheparin plasma allowed to stand at room temperature (21 degrees C) for 2 h, before being frozen at -20 degrees C (FFA = 1817 +/- 291 vs. 698 +/- 66 microEq/l, P < 0.005, mean +/- SEM, without and with paraoxon, respectively); and b) in postheparin plasma immediately stored at -20 degrees C (FFA = 2682 +/- 357 vs. 1299 +/- 150 microEq/l, P < 0.005, without and with paraoxon, respectively). No difference in the FFA level was found in preheparin plasma collected either with or without paraoxon when: a) the samples were placed in ice and immediately assayed; b) the specimens were immediately frozen at -70 degrees C and assayed 60 days later.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of techniques to obtain plasma for measurement of levels of free fatty acids. 835 49

A choline amperometric biosensor was assembled and used to measure the anticholinesterase activity due to compounds (which have the property to inhibit cholinesterase enzymes) present in water samples. This parameter can be used as a 'toxicological index', defined as the amount of compound which causes a certain percentage of cholinesterase inhibition equivalent to a known amount of a reference compound causing the same percentage inhibition. The organophosphorus insecticide Paraoxon, which has proved to be a strong inhibitor of cholinesterase enzymes, was chosen as the reference compound. The analysis was carried out by monitoring the decrease of cholinesterase activity in the presence of a pesticide and a substrate specific for the enzyme whose reaction produces choline. The decrease in choline production was measured by the choline sensor and correlated to the concentration of anticholinesterase compound present in the solution. Parameters such as buffer, pH, temperature and incubation time were optimized. The rate constant Ki was calculated experimentally for Paraoxon and used in the anticholinesterase activity measurements at different fixed incubation times. The probe was calibrated with different standard solutions of Paraoxon. The effect of Paraoxon and heavy metals on the choline probe was evaluated. This probe was then used for the determination of anticholinesterase activity of some organophosphorus pesticides, and heavy metals in spiked waters. Samples were also analysed by liquid/liquid extraction and GC determination. Results seem to correlate with acute toxicity expressed as LD50 (oral, rat). Analysis of water samples from different sources in central Italy were analysed for total anticholinesterase activity (TAA) and compared with a reference procedure.
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PMID:Anticholinesterase activity measurement by a choline biosensor: application in water analysis. 839 50

Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic metabolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate). The effects of organophosphorus compounds on peripheral synapses have been attributed to inhibition of cholinesterase and to direct actions on muscarinic and nicotinic receptors, but less is known about the actions of organophosphorus compounds, including paraoxon, in the central nervous system. We investigated initially the effects of paraoxon on spontaneous transmitter release by recording miniature postsynaptic currents (MPSCs) from cultured rat hippocampal neurons using the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 microM) in the presence of tetrodotoxin (0.3 microM) and atropine (1 microM) caused a significant increase in the frequency of gamma-aminobutyric acid- and glutamate-mediated MPSCs, but did not change the peak amplitudes or decay-time constants of these MPSCs. In contrast, application of nicotinic agonists or antagonists did not change the MPSC frequency. The presynaptic effect of paraoxon shown here was not mediated by actions on muscarinic or nicotinic receptors, or by elevated acetylcholine levels secondary to inhibition of cholinesterase. In addition, agonists were applied to assess the postsynaptic effects of paraoxon on excitatory and inhibitory amino acid receptors. Paraoxon (30 microM-1 mM) blocked the ion channels of glycine, gamma-aminobutyric acidA, N-methyl-D-aspartic acid and nicotinic acetylcholine receptors, but not the ion channels of kalnate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. The combined effects of paraoxon on spontaneous transmitter release and on the functions of several ligand-gated receptors may constitute mechanisms relevant to the neurotoxicity of paraoxon.
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PMID:Paraoxon: cholinesterase-independent stimulation of transmitter release and selective block of ligand-gated ion channels in cultured hippocampal neurons. 881

Recent reports indicate that organophosphate insecticides, in addition to inhibiting acetylcholinesterase activity, can bind directly at a subset of muscarinic receptors, which also bind cis-methyldioxolane with high affinity. Muscarinic receptors are known to act through at least two second messenger systems, either the stimulation of phosphoinositide turnover (mediated through the M1 and M3 receptor subtypes) or the inhibition of cAMP formation (mediated through the M2 and M4 receptor subtypes). We have investigated the action of the active forms of parathion, malathion, and chlorpyrifos (paraoxon, malaoxon, and chlorpyrifos oxon, respectively) on these second messenger systems in cortical slices from adult male Long-Evans rats. Paraoxon, malaoxon, and chlorpyrifos oxon (10(-8) to 10(-4) M) inhibited forskolin-stimulated cAMP formation in a concentration-dependent manner. The effect on cAMP formation was blocked by the muscarinic antagonist atropine (10 microM). These results suggest that paraoxon, malaoxon, and chlorpyrifos oxon can act as agonists at the M2 and/or M4 subset of muscarinic receptors. In addition, chlorpyrifos may have another site of action. In contrast, none of the organophosphates had any effect on basal or carbachol-stimulated phosphoinositide hydrolysis. The differential activity on these two second messenger systems make it unlikely that the observed effects on cAMP formation are due to increases in endogenous acetylcholine resulting from inhibition of acetylcholinesterase.
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PMID:Organophosphorus compounds preferentially affect second messenger systems coupled to M2/M4 receptors in rat frontal cortex. 884 8

1. Multiple low doses of the direct acting organophosphates, ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and ecothiopate than for mipafox. 2. Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity. 3. Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase. 4. These results have particular implication for the use of multiple low doses of organophosphates occupationally by man.
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PMID:The effects of multiple low doses of organophosphates on target enzymes in brain and diaphragm in the mouse. 905 10

Tazarotene is a novel acetylenic retinoid for the treatment of psoriasis and acne. We examined (1) the hydrolysis of tazarotene in blood from Japanese-American and Caucasian subjects, (2) the esterases responsible for this hydrolysis in human blood, and (3) tazarotene hydrolysis in rat and human liver microsomes. Tazarotene hydrolysis and enzyme inhibition were assessed by monitoring the disappearance of tazarotene and the appearance of its primary metabolite tazarotenic acid by HPLC. In blood, tazarotene was converted mainly to tazarotenic acid via first-order kinetics, and there was no statistically significant difference in the hydrolytic (metabolic) rate of tazarotene in uninhibited Japanese-American and Caucasian blood. Physostigmine (a cholinesterase inhibitor), bis(p-nitrophenyl) phosphate (a carboxylesterase inhibitor), and EDTA (an aromatic esterase inhibitor) did not significantly affect tazarotene hydrolysis in blood. Paraoxon, an inhibitor of all serine esterases including cholinesterase and carboxylesterase, decreased the hydrolysis of tazarotene to tazarotenic acid by 95% in both blood and liver microsomes. In conclusion, blood and liver esterases play a significant role in the hydrolysis of tazarotene to tazarotenic acid, and paraoxon-inhibitable forms of esterases are involved in this hydrolysis in humans.
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PMID:Metabolic deesterification of tazarotene in human blood and rat and human liver microsomes. 926 78

1. The effects of two model inducers of the cytochrome P450 system, phenobarbital (PB) and beta-naphthoflavone (NF), on the toxicity of paraoxon were studied in rats. 2. Paraoxon toxicity was measured by inhibition of brain acetylcholinesterase (AChE) activity. 3. PB treatment did not affect the toxicity of paraoxon, whereas NF increased the inhibition of brain AChE. PB administration slightly increased the activities of some peripheral cholinesterases and carboxylesterases, as well as liver microsomal paraoxonase (Pxase). 4. NF administration, in contrast, decreased the activities of peripheral esterases. Serum Pxase activity was reduced by both inducers. 5. Hepatic CYP2B and CYP1A were markedly induced by PB and NF, respectively. 6. Cytochrome P450 isoenzymes induced by PB or NF seemed not to be critical in the detoxification of paraoxon in vivo. NF caused a general reduction of peripheral esterases, which led to an increase in paraoxon toxicity. 7. The results indicated the great importance of peripheral cholinesterases and carboxylesterases as a detoxifying mechanism of paraoxon. The role of serum paraoxonase was not critical.
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PMID:Effect of phenobarbital and beta-naphthoflavone on activities of different rat esterases after paraoxon exposure. 968 78


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