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)

Organophosphorus esters have the potential to produce several forms of toxicity. Most produce acute intoxication as a result of inhibition of acetylcholinesterase and, if severe, this can have longer lasting secondary consequences such as intermediate syndrome, or even permanent disability. Some esters produce a very specific syndrome of delayed peripheral neuropathy. This neuropathy is always preceded by severe acute intoxication, except in the case of a few specific agents such as tri-o-cresyl phosphate. All of these effects are reasonably well understood and show a dose threshold. Chronic low level exposure in non-poisoned subjects has been associated with impaired neurobehavioral performance in some, but not all, epidemiological studies. The mechanisms involved are not well understood, but if organophosphates do play a causal role, this will not necessarily be via acetylcholinesterase inhibition. Doses too low to produce cholinergic signs have been shown to produce a variety of effects in experimental animals ranging from enhanced maze learning to slowed nerve conduction. It is likely that other, more sensitive, brain proteins are the targets for such actions. Effects mediated via such target proteins would be expected to show very different structure-activity relationships to acute toxicity mediated by acetylcholinesterase. Hence epidemiological studies expecting similar (class) effects from low-dose exposure to different organophosphorus esters may produce variable results or false negatives.
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PMID:The potential for toxic effects of chronic, low-dose exposure to organophosphates. 1132 93

Occupational exposure to organophosphorus insecticides (OPs), such as chlorpyrifos, may be monitored by the measurement of the activity of peripheral cholinesterase (ChE) enzymes, including erythrocyte acetylcholinesterase (EAChE) and serum cholinesterase (SChE). Lymphocyte neuropathy target esterase (NTE) is thought to have potential as a predictor of organophosphate-induced delayed neuropathy (OPIDN). This paper describes work performed in 39 Australian pest control operators (PCOs) exposed to a termiticide containing chlorpyrifos, and 34 unexposed control subjects. EAChE activities in PCOs did not differ from those of unexposed control workers. Mean NTE activity was slightly higher in PCOs than in controls and mean SChE was 52% of control activity. These results indicate that exposure of Australian PCOs to termiticides containing chlorpyrifos may be monitored using SChE but not EAChE or NTE, and that workers in this industry have sufficiently high OP exposure to significantly depress SChE activity. SChE inhibition of 70-80% may be associated with symptoms. Although no current symptoms were reported to be associated with occupational OP exposure, these workers may be at increased risk of acute effects following inadvertent spills or self-contamination due to their background level of exposure to OPs. While it is preferable to compare ChE enzyme activities between pre- and post-exposure periods to evaluate OP-related effects in individuals, in some cases there is an absence of pre-exposure data. The results of this study suggest that a screening value for SChE of 550 nmol/min/ml in a single blood sample may be useful to identify potentially OP-exposed individuals in the Australian population. Australian control subjects were similar with respect to EAChE, but displayed activities of NTE and SChE approximately 50 and 23% lower than an unexposed UK reference group. While these comparisons are presently speculative, they suggest that there may be differences in SChE and NTE activities in control populations of the two countries. The routine treatment of Australian homes with termiticides containing OPs, or differences in the availability and use of domestic OP-containing insecticides may explain these population differences. Further work is required to examine whether these differences are real, and if so their likely cause.
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PMID:Peripheral cholinesterase inhibition by occupational chlorpyrifos exposure in Australian termiticide applicators. 1171 58

Gulf War veterans were given pyridostigmine bromide (PB) tablets to enhance the therapeutic effect of antidotes to nerve agents in the event of exposure. The goal of this research is to examine whether combined exposure to PB and sarin (agent GB) is more neurotoxic to sensitive surrogate animals, mice and chickens, than if given separately. Scoping trials were performed to establish appropriate dose-response ranges for sarin and control chemicals. IC50 values were determined in chickens and mice for in vitro inhibition of acetylcholinesterase (AChE) and neuropathy target esterase (NTE). The results indicated PB neither inhibits NTE nor does it spare sarin's inhibition of AChE. Chick embryo nerve cells in vitro showed more inhibition of AChE activity and no faster recovery when PB treatment was followed by DFP treatment than the other way around. Experiments on chickens also indicated that PB treatment did not inhibit NTE and that it crossed the blood brain barrier inhibiting brain AChE although to a lesser extent than it inhibited blood cholinesterases. Other experiments determined multiple dose levels in chickens for sarin and DFP that inhibited > 80% of NTE, considered a threshold for triggering organophosphate-induced delayed neuropathy.
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PMID:Actions of pyridostigmine and organophosphate agents on chick cells, mice, and chickens. 1202 98

Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages of chickens. All birds received toxicants through gavage in a single oral dose between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no birds displayed symptoms of clinical organophosphate-induced delayed neuropathy (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this higher dose, Br.NTE inhibition was similar that presented by Babcock chickens. Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE, when compared to controls. However, Br.NTE was inhibited less than 20%, and there were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than 80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two chickens became totally paralyzed. This finding suggested that chicken strain was important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was necessary but was not sufficient to produce OPIDN in chickens, since babcock and hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without clinical signs of OPIDN.
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PMID:Organophosphate induced delayed neuropathy in genetically dissimilar chickens: studies with tri-ortho-cresyl phosphate (TOCP) and trichlorfon. 1242 64

Many compounds, including some pesticides, contain structural centres of asymmetry, which convey the property of a type of stereoisomerism known as chirality. Such compounds can exist in two or more forms, depending on the number of chiral atoms and are termed stereoisomers or enantiomers. Stereoisomers of a particular compound can have different biological properties; one such of particular importance for toxicological evaluation, is the potential for differences in metabolic disposal of and binding of stereoisomers to molecular targets in the cell. The combination of differential metabolism of chiral organophosphorus (OP) pesticides and opposing stereoselectivity of inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE) can affect the value of the hen test, performed to OECD guidelines, in predicting the potential to cause organophosphate-induced delayed polyneuropathy (OPIDP) in humans. This is a mixed central and sensory and motor neuropathy. The experimental data on structural analogues of the pesticide methamidophos and the evidence for stereoselective OPIDP are reviewed and a model is given demonstrating how the properties of a chiral OP can result in the neuropathic potential not being detected by the standard hen test. A strategy for the assessment of a racemic mixture comprised of two OP enantiomers for the potential to induce OPIDP is outlined. The strategy uses information from structure activity relationships (SAR), in vitro tests and in vivo tests to allow risk assessment decisions to be made. It is suggested that the potential for stereoselective toxicity of pesticides should be routinely considered in regulatory assessments.
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PMID:Toxicological assessment of isomeric pesticides: a strategy for testing of chiral organophosphorus (OP) compounds for delayed polyneuropathy in a regulatory setting. 1520 78

Small-diameter sensory nerves innervating the skin are responsive to noxious stimuli, and an injury to these nerves is presumably related to neuropathic pain. Injury-induced neuropathic pain in animals can be produced by laser irradiation, which usually requires concomitant use of photosensitive dyes, known as the photochemical approach. It is not clear whether laser irradiation alone can induce neuropathic pain. In addition, two issues are important to apply these approaches: the relationship between the extent of laser irradiation and the occurrence of neuropathic pain, and the susceptibility of small-diameter sensory nerves in the skin to laser-induced neuropathic pain. To address these issues, we designed a new model of focal neuropathy by applying a diode laser of 532 nm (100 mW) to the sciatic nerve and evaluated small-diameter nerves by quantifying skin innervation and large-diameter nerves by measuring amplitudes of the compound muscle action potential (CMAP). Immediately after laser irradiation, epineurial vessels were occluded due to the formation of thrombi, and the blood flow through these vessels was markedly reduced. On postoperative day (POD) 2, animals developed characteristic manifestations of neuropathic pain, including spontaneous pain behaviors, thermal hyperalgesia, and mechanical allodynia. These phenomena peaked during PODs 7-21, and lasted for 3-6 weeks. The neuropathology at the irradiated site of the sciatic nerve included a focal area of axonal degeneration surrounded by demyelination and endoneurial edema. The extent of damage to large-diameter motor and sensory nerves after laser irradiation was evaluated by nerve conduction studies. On the irradiated sides, amplitudes of the compound muscle action potentials and sensory nerve action potentials (SNAPs) were reduced to 65.0% (P < 0.0001) and 42.5% (P < 0.01) of those on the control sides, respectively. Motor innervation of the neuromuscular junctions (NMJs) on plantar muscles was examined by combined cholinesterase histochemistry and immunohistochemistry. The ratio of innervated NMJs on the operated sides decreased to 76.3% of that on the control side. Skin innervation in the territory of the irradiated sciatic nerves was evaluated by immunohistochemistry with neuronal markers. Among these markers, epidermal nerve densities for protein gene product (PGP) 9.5, calcitonin gene-related peptide (CGRP), and substance P (SP) were significantly lower on the irradiated sides than the control sides with a different degree of loss for each marker (42.1-53.1%, P < 0.05). Results suggest that laser-induced focal neuropathy provides a new system for studying neuropathic pain. With this approach, the extent of nerve injury can be quantified. Both small-diameter epidermal nerves and large-diameter sensory and motor nerves are susceptible to laser-induced injury of different degrees.
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PMID:Skin denervation, neuropathology, and neuropathic pain in a laser-induced focal neuropathy. 1564 95

Uro-neurological assessment was performed in four patients with small-fiber neuropathy due to amyloidosis (2 transthyretin-type/2 immunoglobulin light-chain-type). Voiding difficulties were due to detrusor weakness and impaired bladder sensation. In two patients cholinesterase inhibition treatment caused urge incontinence, indicating detrusor denervation supersensitivity. The underlying mechanisms of urinary dysfunction seem to involve postganglionic cholinergic and afferent somatic nerves.
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PMID:Urinary dysfunction and autonomic control in amyloid neuropathy. 1647 99

Numerous approaches have been studied to degrade organophosphorus (OP) compounds and ameliorate their toxicity. In the current study, the potential of genetically engineered organophosphorus hydrolase (OPH) enzymes to functionally biotransform OP neurotoxicants was examined by assessing effects of OPH-hydrolyzed OPs on acute and delayed indicators of neurotoxicity. SY5Y human neuroblastoma cells were used as a model test system, as these cells respond distinctly to mipafox, which produces OP-induced delayed neuropathy, and paraoxon, which does not. Short-term effects of four OPH-treated OPs on acetylcholinesterase (AChE) and neuropathy target esterase (NTE) activities were measured in retinoic acid-differentiated or undifferentiated cells, and delayed effects of OPH-treated paraoxon or mipafox on levels of neuronal cytoskeletal proteins in nerve growth factor (NGF)-differentiated cells. The anti-AChE activity of paraoxon (maximum 3 muM) and anti-NTE activity of mipafox (250 muM) in SY5Y cells were prevented by biodegradation with OPH. Anti-AChE activities of mipafox, methyl parathion, and demeton-S were partially ameliorated, depending on OP concentration. Intracellular amounts of the 200-kD neurofilament protein NF200 were unchanged after treatment with OPH-treated or buffer-treated paraoxon, as expected, as this endpoint is insensitive to paraoxon. However, NF200 levels rose in cells treated during late differentiation with OPH-treated mipafox. This finding suggests the existence of a threshold concentration of mipafox below which SY5Y cells can maintain their viability for compensating cellular damage due to mipafox in neurite elongation. These results indicate that OPH may be used to biodegrade OPs and remediate their neurotoxic effects in vitro and that AChE and NTE are suitable detectors for OPH amelioration.
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PMID:Degradation of organophosphorus neurotoxicity in SY5Y neuroblastoma cells by organophosphorus hydrolase (OPH). 1676 77

Carbamates are reversible inhibitors of acetylcholinesterase, and some also inhibit neuropathy target esterase (NTE), the target in organophosphate-induced delayed polyneuropathy. However, based on mechanistic considerations, these carbamates were thought to be unable to initiate polyneuropathy. Consequently, clinical reports of polyneuropathy associated with carbamate exposures have been disregarded. We discuss three cases of polyneuropathy that occurred after severe poisoning by methylcarbamates. In addition, high repeated doses of phenyl N-methyl N-benzylcarbamate caused nearly 100% NTE inhibition and polyneuropathy in the hen model. These data suggest the need to reconsider the long-standing tenet that carbamates cannot cause polyneuropathy. Alternatively, a preexisting subclinical neuropathy in these individuals may have been amplified by carbamates, as observed in animal models. We suggest that individuals with underlying neuropathy (e.g., diabetics) who are poisoned by carbamates should be followed closely. In addition, procedures for the current risk assessment of carbamate pesticides may need to be reconsidered.
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PMID:Do carbamates cause polyneuropathy? 1689 62

Two terrorist attacks with the nerve agent Sarin affected citizens in Matsumoto and Tokyo, Japan in 1994 and 1995, killing 19 and injuring more the 6000. Sarin, a very potent organophosphate nerve agent, inhibits acetylcholinesterase (AchE) activity within the central, peripheral, and autonomic nervous systems. Acute and long-term Sarin effects upon humans were well documented in these two events. Sarin gas inhalation caused instantaneous death by respiratory arrest in 4 victims in Matsumoto. In Tokyo, two died in station yards and another ten victims died in hospitals within a few hours to 3 months after poisoning. Six victims with serum ChE below 20% of the lowest normal were resuscitated from cardiopulmonary arrest (CPA) or coma with generalized convulsion. Five recovered completely and one remained in vegetative state due to anoxic brain damage. EEG abnormalities persisted for up to 5 years. Miosis and copious secretions from the respiratory and GI tracts (muscarinic effects) were common in severely to slightly affected victims. Weakness and twitches of muscles (nicotinic effects) appeared in severely affected victims. Neuropathy and ataxia were observed in small number (less than 10%) of victims, which findings disappeared between 3 days and 3 months. Leukocytosis and high serum CK levels were common. Hyperglycemia, ketonuria, low serum triglyceride, hypopotassemia were observed in severely affected victims, which abnormalities were attributed to damage of the adrenal medulla. Oximes, atropine sulphate, diazepam and ample intravenous infusion were effective treatments. Pralidoxime iodide IV reversed cholinesterase and symptoms quickly even if administered 6 h after exposure. Post Traumatic Stress Disorder (PTSD) was less than 8% after 5 years. However, psychological symptoms continue in victims of both incidents. In summary, both potent toxicity and quick recovery from critical ill conditions were prominent features. Conventional therapies proved effective in Sarin incidents in Japan.
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PMID:Sarin experiences in Japan: acute toxicity and long-term effects. 1696 40


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