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)

Cholinesterases are ubiquitous carboxylesterase type B enzymes capable of hydrolyzing the neurotransmitter acetylcholine which are transiently expressed in multiple germline, embryonic, and tumor cells. The acute poisoning effects of various organophosphorous compounds are generally attributed to their irreversible covalent interaction with cholinesterases and block of their catalytic activities. We have recently found a de novo inheritable amplification of a CHE gene encoding defective butyrylcholinesterase (acylcholine acyl hydrolase; EC 3.1.1.8) in a family under prolonged exposure to the agricultural organophosphorous insecticide methyl parathion. Further analysis revealed that both the CHE and the ACHE genes, encoding acetylcholinesterase (acetylcholine acetyl hydrolase; EC 3.1.1.7), are amplified in leukemias and platelet disorders and that the tumorigenic expression of these genes in ovarian carcinomas is associated with their frequent coamplification in these tumors. The amplification of CHE and ACHE genes in normal and tumor tissues might be analogous to the well-known amplification of other genes encoding target proteins to toxic compounds. As such, it could provide cells a selection advantage when exposed to organophosphorous poisons. Further, since cholinesterases appear to play developmentally important roles in multiple cell types, the amplification and overexpression of their corresponding genes might affect fertility, be related to the progression of various tumor types, and bear upon the ecological and clinical risks involved with the common use of organophosphorous poisons.
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PMID:Amplification of butyrylcholinesterase and acetylcholinesterase genes in normal and tumor tissues: putative relationship to organophosphorous poisoning. 240 80

The effect of the microsomal enzyme inducer beta-naphthoflavone (beta NF) on the development of organophosphorus-induced delayed neuropathy (OPIDN) was examined in two laboratories (VPI and MSU), utilizing two strains of White Leghorn hens. A single intraperitoneal injection of beta NF at 80 mg/kg body weight 48 h prior to administration of o-tolyl saligenin phosphate (TSP), the neuroactive metabolite of tri-o-tolyl phosphate (TOTP), caused a significant increase in hepatic microsomal cytochrome P-450 concentrations and aniline hydroxylase activities after 72 h in both strains. Hepatic carboxylesterase and cholinesterase activities were not affected by beta NF treatment in either strain. Administration of TSP in single subcutaneous doses of 20 and 25 mg/kg body weight (VPI) or 30 and 60 mg/kg body weight (MSU) caused significant inhibition of whole-brain neuropathy target esterase (NTE) activity 24 h postdosing, and hens subsequently developed clinical signs characteristics of OPIDN. beta NF had no significant effect on NTE inhibition or on initiation or severity of OPIDN clinical signs. However, OPIDN clinical signs were less severe in the strain of bird (MSU) with the higher intrinsic hepatic carboxylesterase activity and the higher beta NF-induced cytochrome P-450 concentration. The study indicates that microsomal enzyme induction, which has been shown to alleviate TOTP-induced delayed neuropathy, could not alleviate OPIDN resulting from exposure to TSP. This study also suggests that strain may affect susceptibility to TSP-induced delayed neuropathy.
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PMID:Effect of beta-naphthoflavone on o-tolyl saligenin phosphate-induced delayed neuropathy in two lines of chickens. 259 76

The dose-response (0.1 to 1000 mg/kg sc) effects of 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP; a metabolite of the organophosphorus compound tri-o-cresylphosphate) on total cholinesterase (ChE) and carboxylesterase (CaE) activities in tissues from the rat were examined. Doses of CBDP greater than 1.0 mg/kg inhibited CaE activity maximally (greater than 99%) in plasma and lung, two important sites for detoxification of organophosphorus toxicants. A biphasic dose-dependent inhibition of ChE activity was seen in all tissues; the ED50 values showed a difference of two orders of magnitude between the first and the second phases of the dose-response curves. CBDP inhibited the blood esterases in the order plasma CaE much greater than plasma ChE much greater than red blood cell (RBC) ChE. The biphasic dose-response curve and preferential inhibition of the blood esterases may reflect the inhibition of butyrylcholinesterase in preference to acetylcholinesterase in these tissues. At doses of CBDP below 1.0 mg/kg, plasma, RBC, and brain regional ChE activities were inhibited by less than 10%, whereas at doses above 2.0 mg/kg, ChE activities were inhibited substantially (up to 80% in plasma, up to 60% in RBC, and greater than 90% in brain regions). On the basis of these results, a dose of CBDP between 1.0 and 2.0 mg/kg should prove useful as a pretreatment for studies of OP toxicity in the rat.
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PMID:The effect of 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide on tissue cholinesterase and carboxylesterase activities of the rat. 261 89

Pretreatment of rats with the nonspecific esterase inhibitor iso-OMPA (1 mg/kg sc) 1 h prior to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate, 0.5 mg/kg sc) administration potentiated carbofuran toxicity by more than threefold. Neither iso-OMPA nor carbofuran in the given doses produced any gross toxic signs. Rats receiving combined treatment, however, showed severe hypercholinergic signs (salivation, tremors, muscle fasciculations, and convulsions) within 5-10 min following carbofuran administration, and the severity was comparatively greater than that observed with an acute dose of carbofuran (1.5 mg/kg sc). Rats pretreated with iso-OMPA (0.5 mg/kg) died within 10-15 min following the acute dose of carbofuran (1.5 mg/kg). Each drug when given alone (1.0 mg/kg iso-OMPA, 0.5 mg/kg carbofuran) caused a significant (p less than .01) inhibition of carboxylesterase (CarbE) activity in brain structures (cortex, stem, striatum, and hippocampus), skeletal muscle (hemidiaphragm), liver, and plasma, whereas acetylcholinesterase (AChE) activity remained significantly (p greater than .01) unchanged. The maximal CarbE inactivation in plasma (less than 14% remaining activity) following either drug indicated a tremendous nonspecific binding to non-AChE serine-containing enzymes. iso-OMPA pretreatment markedly potentiated carbofuran's anticholinesterase activity both in neuronal and in nonneuronal tissues. It can be concluded that iso-OMPA pretreatment potentiates carbofuran toxicity either by preventing nonspecific binding of carbofuran to CarbE and/or possibly by inhibiting its detoxification.
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PMID:Concerted role of carboxylesterases in the potentiation of carbofuran toxicity by iso-OMPA pretreatment. 270 39

In high spinal cats, the acute time-dependent changes of both the activity of spinal reflex pathways and the activity of three different esterases (acetylcholinesterase, carboxylesterase and neurotoxicant target enzyme) in the spinal cord were investigated after intravenous application of the organophosphorus compound di-isopropyl phosphofluoridate (DFP). There is no general depression of spinal reflexes by DFP. While the recurrent inhibition is completely abolished for a long time and the reflexes to a flexor (PBSt) are depressed but with a shorter recovery time, the reflexes to an extensor (GS) are distinctly less depressed or even facilitated. Reflex pathways from skin afferents to motoneurones did not react in a uniform way to DFP, e.g. inhibitory nociceptive pathways were less affected than excitatory ones. Esterase activities were heavily depressed and recovered with different time courses. The acute DFP action cannot be explained by a uniform intoxication of all spinal functions but probably emerges from a differential action on different interneuronal systems.
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PMID:Influence of the organophosphorus compound DFP on inhibitory motor systems and esterase activity in the spinal cord of cats. 271 Apr 27

Initially, mice were pretreated with atropine (17.4 mg/kg; IP) and the oxime reactivator HI-6 (50 mg/kg; IP) 5 min prior to an injection of soman (287 micrograms/kg, SC); approximately 2.1 x LD50 dose). More than 95% of the mice survived this dose of soman with atropine and HI-6 pretreatment. In these survivors of soman poisoning the return of the soman LD50 value to control value (124 micrograms/kg, SC) was determined at various times after the initial soman exposure. Mice which survived exposure to a lethal dose of soman by pretreatment with atropine and HI-6 were sensitized to the lethal effects of soman upon reexposure. The SC soman LD50 at 4 h, after surviving the initial soman exposure, was 20 micrograms/kg. The normal soman LD50 (as evidenced by a LD50 value which was not significantly different from the control value) returned within 4 days, at which time there was still extensive acetylcholinesterase inhibition in all brain regions (striatum, pons-medulla, cerebellum, hypothalamus, hippocampus), diaphragm and erythrocytes. Serum carboxylesterase recovered to control levels within 48 h, whereas liver carboxylesterase activity was not inhibited following the initial soman exposure. The results demonstrate that there is an excess of acetylcholinesterase which is required for normal response in the toxicological sense.
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PMID:Survivors of soman poisoning: recovery of the soman LD50 to control value in the presence of extensive acetylcholinesterase inhibition. 273 Mar 40

The toxicity of soman was investigated in the rat with and without pretreatment with cresylbenzodioxaphosphorin oxide (CBDP). Without pretreatment, the 24-h LD50 for soman was 118.2 micrograms/kg s.c., and soman inhibited carboxylesterase (CaE) activity in plasma (ED50 of 55 micrograms/kg) and cholinesterase (ChE) activity in brain regions (ED50 values of 65-105 micrograms/kg) in a dose-related manner. With pretreatment, the 24-h LD50 for soman was reduced by approximately 6-fold and 8-fold (by 1.0 mg/kg and 16.0 mg/kg of CBDP, respectively), and the ED50 values for soman-induced inhibition of ChE activity in brain regions were reduced by approximately 10-fold (by 1.0 mg/kg of CBDP). The dose-dependent severity of soman intoxication varied widely in rats treated with soman alone but not in CBDP-pretreated rats, and the ED50 for the occurrence of signs of soman intoxication was reduced approximately 7-fold following CBDP (1.0 mg/kg) pretreatment. These data support the hypothesis that CBDP pretreatment effectively blocks tissue CaE sites which serve to detoxify soman, thus potentiating both the soman-induced inhibition of ChE in the CNS and the lethality of soman.
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PMID:Cresylbenzodioxaphosphorin oxide pretreatment alters soman-induced toxicity and inhibition of tissue cholinesterase activity of the rat. 274 82

1. Hydrolysis of the drug esters procaine, chloramphenicol succinate, and prednisolone succinate was studied. Addition of soman to guinea pig liver microsomes caused a dose-dependent inhibition of hydrolysis of all three substrates; at the highest soman concentration (1 microM), ester hydrolysis was totally abolished. 2. Ester hydrolysis was also measured in liver microsomes from guinea pigs pretreated with soman at a low dose (10% of LD50) or at a high dose (90% of LD50) either 1 h or 12 h before killing. Plasma-cholinesterase activity was decreased in all pretreated animals. Liver carboxylesterase activity, measured with the three drug substrates and by hydrolysis of 4-nitrophenyl acetate was increased by all pretreatments. 3. This enhancing effect varies with the substrate and increases with dose of soman. The 12 h pretreatment produced a greater increase in activity than did the 1 h pretreatment. 4. These studies indicate that soman is a potent inhibitor of carboxylesterase activity in vitro but increases the activity of the liver enzyme when administered in vivo.
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PMID:Alteration of hepatic carboxylesterase activity by soman: inhibition in vitro and enhancement in vivo. 275 15

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC) which are microsomal enzyme inducers, and methyl iodide (MeI), cobalt chloride (CoCl2) and tri-o-cresyl phosphate (TOCP) which are inhibitors of the enzymes glutathione transferase, cytochrome (cyt) P-450 and carboxylesterase, respectively, and then challenged with soman (i.p.) to know its LD50. Pretreatment with PB and MC increased and TOCP decreased, whereas MeI as well as CoCl2 did not alter the LD50 value of soman in rats. The 1/2 LD50 dose of soman did not affect the liver microsomal cyt P-450 level, but significantly lowered carboxylesterase (CaE) and cholinesterase (ChE) activities in liver microsomes and in blood plasma. Induction of plasma CaE was more important than microsomal CaE in PB-mediated protection against soman toxicity. Gel filtration of plasma into four protein fractions for their relative soman binding capacity showed that a high-molecular-weight protein fraction (180,000 daltons on SDS-PAGE) which had no CaE activity could bind soman 6 times more than the low-molecular-weight CaE-containing protein fraction (60,000 daltons on SDS-PAGE).
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PMID:Role of carboxylesterase in protection against soman toxicity. 276 74

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.
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PMID:Neuropathy target esterase in hens after sarin and soman. 276 93


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