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)

In the present study, the whole-cell mode of the patch-clamp technique was applied to neurons of the CA1 pyramidal layer of rat hippocampal slices to investigate the effects of the organophosphate (OP) sarin on field stimulation-evoked and on tetrodotoxin (TTX)-insensitive postsynaptic currents (PSCs) mediated by activation of type A gamma-aminobutyric acid (GABA) receptors or AMPA-type glutamate receptors. At 0.3-1 nM, sarin reduced the amplitude of GABA-mediated PSCs and had no effect on the amplitude of glutamatergic PSCs evoked by field stimulation of neurons synaptically connected to the neuron under study. The effect of sarin on evoked GABAergic PSCs was unrelated to cholinesterase inhibition, was partially reversed upon washing of the neurons with sarin-free external solution, and was mediated by a direct interaction of the OP with muscarinic acetylcholine receptors present on presynaptic GABAergic neurons. Sarin had no effect on the amplitude or kinetics of GABA- or glutamate-mediated miniature postsynaptic currents (MPSCs) recorded in the presence of the Na+-channel blocker TTX (300 nM), indicating that the OP does not interact with GABA(A) or glutamate receptors. Further, sarin did not alter the frequency of GABAergic or glutamatergic MPSCs, a finding that led to the conclusion that this OP does not affect the TTX-insensitive release of neurotransmitters. A selective reduction by sarin of the action potential-dependent release of GABA in the hippocampus can account for the occurrence of seizures in intoxicated subjects.
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PMID:The organophosphate sarin, at low concentrations, inhibits the evoked release of GABA in rat hippocampal slices. 1069 68

Serious intoxications and incidences due to misuse of organophosphorus insecticides (OP) have been reported for over three decades. In this meeting I am talking about the following three topics. (1) Epidemiological studies on the use of OP in Japan, Taiwan and Thailand. The National Research Institute of Police Science (NRIPS) in Japan has published the annual report of the epidemiological studies on the criminal and suicide events. The numbers of the incidence of pesticides are approximately 22%-30% of the total incidences, during 1991 and 1996. The incidence of pesticides has been gradually reduced for past six years. This seems to be influenced by the decrease of the incidences of paraquat having extremely high toxicity. According to the epidemiological data in the National Poison Center in Taiwan, unlike the prevalence of drug poisoning exposures in most western countries, pesticides poisoning exposures are numerous in Taiwan. The number of pesticide intoxication cases is 6,872 out of 23,436 of total case numbers of various intoxications during the 1985 and 1997. The fatality rate is much higher in Taiwan than in most western countries, with 5.65% of all poisoning exposures resulted in death. Paraquot is the leading cause of death in Taiwan. The ratio of death to total OP intoxication cases is 11.5% including accidental exposure and suicide. According to the report of the Division of Epidemiology, Ministry of Public Health, Thailand during the 1990-1995, the overall morbidity due to poisoning was 30 per 100,000 population with 300 deaths per year. The morbidity rate of reported pesticide poisoning in the whole country was 10 per 100,000 population. (2) Sarin victims in Tokyo. On March 20, 1995, a terrorist attack using sarin (isopropylmethylphosphonofluoridate) occurred on the Tokyo subway. Many people inhaled the sarin gas and collapsed in the train. Eventually, 12 people died and over 5,000 were injured. The results of the forensic studies showed that methylphosphonic acid, the hydrolysis product of sarin, bound to AChE in the cerebellums of the victims was separated and identified using GCMS. (3) A sensitive and rapid biomarker of OP-poisoning. Beta-glucuronidase (beta-G) is loosely bound to egasyn which is one of carboxylesterase isozymes in the liver microsomes. The oxon formed from OP in the liver microsomes is covalently bound to egasyn and causes the cleavage of the egasyn-glucuronidase complex, leading to the release of beta-G into the blood. In fact, plasma beta-G activities is a much more sensitive and rapid biomarker than the blood cholinesterase inhibition. In conclusion, OPs cause serious toxicity in both acute and chronic exposures. The epidemiological data in Taiwan and Thailand show that paraquat intoxication cause the most serious irreversible damage in the patients. In 1995, terrorists attack using sarin which is one of the most toxic OP, on the Tokyo subway, and 12 people died. This is an example of the acute intoxication of OP and some people have been still in hospitalized. Recently, the present authors have reported that the plasma beta-G activity is a novel biomarker of OP intoxication. The plasma beta-G is rapidly and significantly increased after OP exposure, and this is a much more sensitive to OP intoxication than ChE inhibition.
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PMID:Organophosphates and their impact on the global environment. 1079 4

Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.
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PMID:Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats. 1189 84

To examine the effects of occupational and environmental neurotoxicants on vestibular, cerebellar and spinocerebellar functions, the following three groups of subjects were examined, using a computerized posturography with sway frequency analysis: (1) 49 male chemical factory workers exposed to lead stearate, aged 27-63 (mean 43) years, with concurrent blood lead concentrations (BPbs) of 11-113 (mean 48) microg/100 g and past mean BPbs of 7-52 (mean 24) microg/100 g; (2) 29 male sandal, shoe and leather factory workers, aged 35-73 (mean 51) years, with urinary 2,5-hexanedione (HD) concentrations of 0.41-3.06 (mean 1.20) mg/g creatinine; and (3) 9 females, aged 19-58 (mean 29) years, who were exposed to sarin accidentally 6-8 months before the study (Tokyo Subway Sarin Poisoning, March 20,1995) and showed plasma cholinesterase (ChE) activities of 13-95 (mean 68) IU/l on the day of poisoning. The pattern of posturographic changes in lead workers suggested that the vestibulocerebellum (lower vermis), anterior cerebellar lobe and spinocerebellar afferent pathway were asymptomatically affected; the vestibulocerebellar change reflected concurrent lead absorption and the anterior cerebellar one reflected past absorption. Similarly, vestibulocerebellar and spinocerebellar functions were affected by n-hexane in solvent workers; the effect on the vestibulocerebellar function was probably inhibited by xylene. Also, the chronic (long-term) effect on the vestibulocerebellar function persisted in acute sarin poisoning. It is thus suggested that the vesitibulocerebellar function is most sensitive to all the three chemicals examined. It appears that the computerized posturography with frequency analysis is a useful technique for assessment of vestibular, cerebellar and spinocerebellar effects in occupational and environmental health.
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PMID:Computerized posturography with sway frequency analysis: application in occupational and environmental health. 1192 10

Pyridostigmine bromide, a reversible anticholinesterase drug, was used by military personnel during the Gulf War. They were under physical stress and might have been exposed to low-dose nerve gas, sarin. This study examined the interactions of low-dose sarin and pyridostigmine in exercised mice. Male NIH Swiss mice were treated as follows: 1) Control; 2) Sarin (0.01 mg/kg, sc); 3) exercise; 4) sarin plus exercise; 5) pyridostigmine; 6) pyridostigmine plus exercise; 7) pyridostigmine plus sarin; 8) pyridostigmine plus sarin plus exercise. Exercise was given daily for 10 weeks on treadmill and pyridostigmine and sarin were administered daily during the 5th and 6th weeks only. Respiratory exchange ratio decreased significantly during the dosing period of 5th and 6th weeks in groups 4, 6, and 8. Animals were sacrificed 24 hours after the ten-week exercise, tissues isolated and analyzed. Sarin significantly decreased butyrylcholine esterase (BChE) activity in plasma; AChE activity in platelet, triceps muscle, and striatum; neurotoxic esterase (NTE) activity in platelets, spinal cord, cortex and striatum and malondialdehyde (MDA) levels in sciatic nerve and cord. Sarin plus exercise significantly reduced BChE activity in plasma; acetylcholinesterase (AChE) activity in platelets, muscle, nerve and striatum; NTE activity in platelets, cord, cortex and striatum; and increased creatinine phosphokinase (CK) activity in plasma and MDA levels in cord. Pyridostigmine plus exercise significantly decrease BChE activity in plasma; AChE activity in muscle and enhanced malondialdehyde (MDA) levels in muscle. Pyridostigmine plus sarin significantly decreased NTE activity in platelets, cord, cortex and striatum. Pyridostigmine plus sarin plus exercise significantly altered AChE activity and MDA levels in muscle; and NTE activity in platelets, nerve, cord and cortex. Exercise significantly augmented the changes in plasma CK activity, muscle and nerve AChE activity, platelet NTE activity and cord MDA levels induced by sarin. It is concluded that physical stress (exercise) enhanced the persistent/delayed toxic effects of low-dose sarin and pyridostigmine in specific tissues of mice.
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PMID:Persistent/delayed toxic effects of low-dose sarin and pyridostigmine under physical stress (exercise) in mice. 1552 54

Acylpeptide hydrolase (APH) unblocks N-acetyl peptides. It is a major serine hydrolase in rat blood, brain, and liver detected by derivatization with (3)H-diisopropyl fluorophosphate (DFP) or a biotinylated fluorophosphonate. Although APH does not appear to be a primary target of acute poisoning by organophosphorus (OP) compounds, the inhibitor specificity of this secondary target is largely unknown. This study fills the gap and emphasizes blood APH as a potential marker of OP exposure. The most potent in vitro inhibitors for human erythrocyte and mouse brain APH are DFP (IC(50) 11-17 nM), chlorpyrifos oxon (IC(50) 21-71 nM), dichlorvos (IC(50) 230-560 nM), naled (IC(50) 370-870 nM), and their analogs with modified alkyl substituents. (3)H-diisopropyl fluorophosphate is a potent inhibitor of mouse blood and brain APH in vivo (ED(50) 0.09-0.2 mg/kg and 0.02-0.03 mg/l for ip and vapor exposure, respectively). Mouse blood and brain APH and blood butyrylcholinesterase (BChE) are of similar sensitivity to DFP in vitro and in vivo (ip and vapor exposure), but APH inhibition is much more persistent in vivo (still >80% inhibition after 4 days). The inhibitory potency of OP pesticides in vivo in mice varies from APH selective (dichlorvos, naled, and trichlorfon), to APH and BChE selective (profenofos and tribufos), to ChE selective or nonselective (many commercial insecticides). Sarin administered ip at a lethal dose to guinea pigs inhibits blood acetylcholinesterase and BChE completely but erythrocyte APH only partially. Blood APH activity is therefore a sensitive marker for exposure to some but not all OP pesticides and chemical warfare agents.
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PMID:Blood acylpeptide hydrolase activity is a sensitive marker for exposure to some organophosphate toxicants. 1588 65

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

We investigated the potential of low-level exposures to the chemical warfare nerve agent, sarin, to produce adverse effects. Rhesus (Macaca mulatta) and African green monkeys (Chlorocebus acthiops) were trained on a serial probe recognition (SPR) task before IM administration of a low-level concentration (5.87 microg/kg or 2.93 microg/kg) of sarin. Blood was sampled before agent administration and at various times following administration. Sarin administration did not disrupt performance on the SPR task in either species. Major dependent measures characterizing performance (accuracy, number of completed trials per session, average choice response time) were largely unaffected on the day sarin was administered as well as on subsequent testing sessions occurring over several weeks following administration. Analyses of red blood cell (RBC) and plasma samples revealed that sarin administration produced a substantial degree of inhibition of circulating acetylcholinesterase (AChE) in RBC fractions and butyrylcholinesterase (BChE) in plasma fractions, which only slowly recovered. In this regard, AChE activity was inhibited to a greater extent than BChE activity. Blood samples were also evaluated for regenerated sarin, which was found in RBC and plasma fractions in both species and showed orderly elimination functions. More sarin was regenerated from RBC fractions than from plasma fractions. Elimination of regenerated sarin was much slower in RBC than plasma and exceeded the expected time of AChE aging, suggesting the presence of additional sarin binding sites. In general, effects were similar in both species. Taken together, our results show that while the concentrations of sarin administered were clearly biochemically active, they were below those that are required to produce a disruption of behavioral performance.
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PMID:Evaluation of cognitive and biochemical effects of low-level exposure to sarin in rhesus and African green monkeys. 1712 68

Presently used methods for detection and diagnosis of the severity of intoxication with organophosphorus (OP) compounds are mostly those that quantify inhibition of blood cholinesterases. It was found that when plasma inhibited with OP compounds is incubated in the presence of a high concentration of fluoride ions, the organophosphate is released from the enzyme thus yielding a phosphofluoridate, which can be analyzed by gas chromatography and NP detection. In our study, the concentration of sarin released after fluoride ions were added to the plasma of sarin-poisoned rats was determined. Sarin amounts in plasma measured after refluoridation and plasma butyrylcholinesterase activity in ten rats, that were exposed to sarin vapors at concentration of 1.25 microg/L (E1 group) and 2.5 microg/L (E2 group) respectively, for 60 min. In the E2 group the concentration of sarin in plasma was nearly 2-fold higher than in the E1 group. These results correspond well with the concentrations of sarin vapors to which the animals were exposed. Both experimental groups of animals showed significant decreases in butyrylcholinesterase activity by more than 30%-36.4% (E1 group) and 47.0% (E2 group). The method of fluoride-induced reactivation provides a very good marker for monitoring sarin intoxication in laboratory animals determined previously mostly by ChE determination which does not allow any information on sarin amounts in plasma.
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PMID:Detection of sarin in plasma of rats after inhalation intoxication. 1719 19

We determined the threshold concentration of sarin vapor exposure producing miosis in African green monkeys (Chlorocebus aethiops). Monkeys (n=8) were exposed to a single concentration of sarin (0.069-0.701mg/m3) for 10min. Changes in pupil size were measured from photographs taken before and after the exposure. Sarin EC50 values for miosis were determined to be 0.166mg/m3 when miosis was defined as a 50% reduction in pupil area and 0.469mg/m3 when miosis was defined as a 50% reduction in pupil diameter. Monkeys were also evaluated for behavioral changes from sarin exposure using a serial probe recognition test and performance remained essentially unchanged for all monkeys. None of the concentrations of sarin produced specific clinical signs of toxicity other than miosis. Sarin was regenerated from blood sampled following exposure in a concentration-dependent fashion. Consistent with a predominant inhibition of acetylcholinesterase (AChE), more sarin was consistently found in RBC fractions than in plasma fractions. Further, elimination of regenerated sarin from RBC fractions was slower than from plasma fractions. Blood samples following exposure also showed concentration-dependent inhibition of AChE activity and, to a lesser extent, butyrylcholinesterase activity. At the largest exposure concentration, AChE inhibition was substantial, reducing activity to approximately 40% of baseline. The results characterize sarin exposure concentrations that produce miosis in a large primate species in the absence of other overt signs of toxicity. Further, these results extend previous studies indicating that miosis is a valid early indicator for the detection of sarin vapor exposure.
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PMID:Determination of miosis threshold from whole-body vapor exposure to sarin in African green monkeys. 1809 90


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