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)

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

Various 4-arylthiomethyl-2-oxo-1,3-dioxole derivatives IIIa-o were synthesized. Their hydrolysis rates by arylesterase (EC 3.1.1.2) and cholinesterase (EC 3.1.1.8) in human serum were evaluated. Some of them were not hydrolyzed by cholinesterase, but were hydrolyzed easily by arylesterase. Among the substrates, sodium 4-((5-methyl-2-oxo-1,3-dioxol-4-yl)methylthio)benzenesulfonate (IIIg) was selected for its substrate reactivity toward arylesterase and its good water solubility. In addition, neither aliesterase (EC 3.1.1.1), acetylesterase (EC 3.1.1.6) nor cholesterol esterase (EC 3.1.1.13) hydrolyzed the compound. IIIg is thus concluded to be a specific substrate for arylesterase. Our assay system for serum arylesterase using IIIg can be readily applied to an automatic analyzer in the diagnosis of liver cirrhosis.
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PMID:2-Oxo-1,3-dioxoles as specific substrates for measurement of arylesterase activity. 193 62

In order to identify non-invasive, biochemical indicators of di(2-ethylhexyl)phthalate (DEHP) exposure, we have compared the effects in blood serum with biochemical effects in liver in rats fed a diet containing 0, 0.25, 0.75 and 2% DEHP for 2 weeks. After 3 days of treatment serum arylesterase activity levels and serum triglycerides were decreased to 60% and 20% of control values, respectively. After a 2-week treatment with DEHP the effects were generally stronger. Compared to a control group, serum arylesterase activity levels, serum triglycerides and serum cholesterol were decreased to 40%, 20% and 50%, respectively. Serum cholinesterase activity levels and serum albumin concentrations were increased by the DEHP treatment to 290% and 135% of control values, respectively. In the livers a hepatomegaly, an induction of cytochrome P-450 IVA1 and induction of the activity of palmitoyl-CoA oxidase and carnitine acetyl-CoA transferase was found to be 180%, 1080%, 1300% and 1700% of control values, respectively. The liver is a more sensitive target for DEHP exposure compared to the biochemical effects in serum, but determination of the serum parameters can be used to determine early biological effects of exposure to DEHP.
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PMID:Effect of di(2-ethylhexyl)phthalate on enzyme activity levels in liver and serum of rats. 227 65

The blood esterase mediating the hydrolysis of esmolol was characterized in several different species including man. In contrast to most ester-containing drugs, hydrolysis of esmolol was mediated by an esterase in the cytosol of red blood cells (RBC) in man and dogs and not in plasma or RBC membrane. Species differences in the esterase activity existed. Guinea pig and rat blood esterase activities were much greater than those in the dog followed by those in man. In addition, the esterase activity in rat and guinea pig blood was localized in plasma and not in RBC. Purified human serum cholinesterase, human RBC membrane acetylcholinesterase, human hemoglobin, human carbonic anhydrases A and B, and human and dog serum albumin were all inactive against esmolol. Esmolol esterase activity in human and dog blood was inhibited by sodium fluoride, EDTA, and p-hydroxymercuribenzoate, but not by echothiophate, eserine, and acetazolamide. In contrast, echothiophate and sodium fluoride, but not eserine, inhibited the esterase activity in rat and guinea pig plasma. Metabolic interaction studies indicated that acetylcholine, succinylcholine, procaine, and chloroprocaine did not interfere with the metabolism of esmolol by human and dog blood. Based on the results, it appeared that an arylesterase in human and dog RBC cytosol mediated the hydrolysis of esmolol while an aliphatic esterase mediated the hydrolysis of esmolol in guinea pig and rat plasma.
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PMID:Biochemical properties of blood esmolol esterase. 286 4

Hydrolysis and covalent binding to nonessential esterases are two biochemical processes which can prevent paraoxon from reacting with the essential enzyme, acetylcholinesterase. Both processes have been proposed as the primary route of paraoxon detoxification in vivo. These experiments were designed to assess the relative contribution of each pathway to the disappearance of paraoxon in the rabbit. In vitro, paraoxon disappeared from whole rabbit blood with a t 1/2 of 17.7 sec. Hydrolysis by paraoxonase (EC 3.1.1.2) accounted entirely for this disappearance and covalent binding contributed essentially nothing. In vivo, following an iv injection of 0.15 mg/kg paraoxon, serum paraoxonase hydrolyzed as much as 41% of the injected dose within the first 30 sec. Pretreatment of rabbits with an ip injection of tri-o-tolyl phosphate eliminated more than 95% of the paraoxon binding sites. However, pretreatment with tri-o-tolyl phosphate had no significant effect on the t 1/2 or volume of distribution of paraoxon, indicating that covalent binding sites did not contribute significantly to the clearance of paraoxon from whole rabbits under these conditions. Hydrolysis of paraoxon by tissue paraoxonases, in addition to that catalyzed by paraoxonase in the blood, could account for its rapid metabolism. These findings demonstrate that paraoxonase has a major role in the disappearance of paraoxon in the rabbit. This suggests that susceptibility of people to chronic paraoxon poisoning may vary, according to their inherited level and type of serum paraoxonase.
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PMID:Paraoxon hydrolysis vs. covalent binding in the elimination of paraoxon in the rabbit. 286 64

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

The effect of dietary exposures to peroxisome-proliferating, hypolipidemic agents on serum esterases was determined in rats and mice. Four genotypes of mice were fed nafenopin (1000 ppm) for six weeks and clofibrate (5000 ppm) was fed to young and aged rats for three weeks. The exposures significantly increased serum cholinesterase activity levels and decreased serum arylesterase activity levels in all groups of both species.
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PMID:Effect of peroxisome proliferating hypolipidemic agents on serum activity levels of arylesterase and cholinesterase in rats and mice. 338 Oct 6

The trichothecene T-2 toxin was rapidly hydrolyzed by rat liver microsomal fraction into HT-2 toxin which was the main metabolite. The metabolism was completely blocked by paraoxon, a serine esterase inhibitor, but not affected by EDTA or 4-hydroxy mercury benzoate, inhibitors of arylesterase and esterases containing SH-group in active site, respectively. Among the serine esterases carboxylesterase (EC 3.1.1.1), but not cholinesterase (EC 3.1.1.8) hydrolysed T-2 toxin to HT-2 toxin. Carboxylesterase activity from liver microsomes was separated into at least five different isoenzymes by isoelectric focusing, and only the isoenzyme of pI 5.4 was able to hydrolyse T-2 toxin to HT-2 toxin. The toxicity of T-2 toxin in mice was enhanced by pre-treatment with tri-o-cresyl phosphate (TOCP), a specific carboxylesterase inhibitor. This confirms the importance of carboxylesterase in detoxification of trichothecenes.
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PMID:Metabolism of T-2 toxin by rat liver carboxylesterase. 370 11

Esterases, hydrolases which split ester bonds, hydrolyse a number of compounds used as drugs in humans. The enzymes involved are classified broadly as cholinesterases (including acetylcholinesterase), carboxylesterases, and arylesterases, but apart from acetylcholinesterase, their biological function is unknown. The acetylcholinesterase present in nerve endings involved in neurotransmission is inhibited by anticholinesterase drugs, e.g. neostigmine, and by organophosphorous compounds (mainly insecticides). Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues. The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites. Aspirin (acetylsalicylic acid), for example, is hydrolysed to salicylate by carboxylesterases in the liver during the first-pass. Only 60% of an oral dose reaches the systemic circulation where it is hydrolysed by plasma cholinesterases and albumin and red blood cell arylesterases. Thus, the concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect. Other drugs have been less extensively investigated than aspirin and these include heroin (diacetylmorphine), suxamethonium (succinylcholine), clofibrate, carbimazole, procaine and other local anaesthetics. Ester prodrugs are widely used to improve absorption of drugs and in depot preparations. The active drug is released by hydrolysis by tissue carboxylesterases. Individual differences in esterase activity may be genetically determined, as is the case with atypical cholinesterases and the polymorphic distribution of serum paraoxonase and red blood cell esterase D. Disease states may also alter esterase activity.
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PMID:Clinical significance of esterases in man. 389 54

Patients with reactive systemic amyloidosis have a reduced ability to degrade amyloid A protein fibrils in vitro. The amyloid A degrading activity in serum has been attributed to a neutral serine protease or proteases. Our results show that patients with reactive systemic (amyloid A) amyloidosis have low activities of two serum esterases, namely, arylesterase and paraoxonase, whereas the activity of a third esterase, cholinesterase, is normal. The combination of reduced arylesterase (less than 55 kU/L) plus reduced paraoxonase activity (less than 35 U/L) was found in 32% of patients with rheumatoid arthritis complicated by amyloidosis, but in only 5% of a control nonamyloid patient group, including patients with rheumatoid arthritis, liver disease, and hypoalbuminemia (p less than 0.001). A significant correlation between serum arylesterase and amyloid A degrading activity was found (patients with rheumatoid arthritis plus amyloidosis, n = 31, r = 0.51, p less than 0.01; all patients, n = 95, r = 0.34, p less than 0.001). Our results suggest that the amyloid A degrading activity may be closely related to the esterase activity in serum.
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PMID:Serum esterase activity in reactive systemic amyloidosis and its relation to amyloid A degrading activity. 609 1


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