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)

Previous studies have shown that a single oral pretreatment of rats with the organophosphorus insecticide 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate (chlorfenvinphos, CVP) afforded protection against the toxicity of a subsequent challenge with the same compound within 24 hr. This protection may be due to the reduction in brain cholinesterase inhibition caused by the decrease in plasma CVP concentration. The purpose of this study was to investigate the mechanism of the decrease in plasma CVP concentration in relation to metabolic induction. CVP was preferentially metabolized by a liver microsomal fraction with an NADPH-generating system, compared with serum or kidney subcellular fractions. A single oral 24-hr pretreatment with CVP (15 mg/kg) increased the oral LD50 of its next dosage to threefold. The same treatment also increased CVP metabolism (to 178%), cytochrome P450 content (to 130%), cytochrome P450 reductase activity (to 130%), cytochrome b5 content (to 121%), and cytochrome P450-linked activities such as aminopyrine demethylase (to 140%) and aniline hydroxylase (to 127%) in the hepatic microsomal fraction. A single oral 24-hr pretreatment of phenobarbital (50 mg/kg), which is known as an inducer of cytochrome P450, increased the oral LD50 of CVP and all the related metabolic parameters listed above in an order of magnitude similar to that of CVP, although the increments induced by the phenobarbital treatment were greater than those induced by the CVP treatment. These results indicate that the increase in hepatic CVP metabolism may be due to the induction of the hepatic cytochrome P450 system caused by the single oral short-term treatment with CVP. This induction may be one of the reasons for the decrease in plasma CVP concentration which may be responsible for the reduction in toxicity of its next dosage.
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PMID:Metabolic induction of the hepatic cytochrome P450 system by chlorfenvinphos in rats. 176 23

The inhibition of cerebral cortex and medulla oblongata acetylcholinesterase and hepatic and plasma aliesterases was studied in female rats following intraperitoneal administration of the phosphorothionate insecticide parathion or its active metabolite paraoxon. Acetylcholinesterase is the target enzyme for organophosphate toxicity while aliesterases are alternative targets for organophosphate inhibition which could serve in a protective capacity during organophosphate intoxication. The effects of pretreatment with cytochrome P450 inducers and inhibitors were also investigated. Pretreatment with phenobarbital slowed the time course of acetylcholinesterase and hepatic aliesterase inhibition following parathion exposure, suggesting the induction of a detoxication pathway(s) to a greater extent than the induction of activation. Although pretreatment with piperonyl butoxide did not affect the rate of acetylcholinesterase inhibition, it slowed hepatic and plasma aliesterase inhibition following parathion administration, presumably from inhibition of the parathion activation pathway. In rats pretreated with beta-naphthoflavone (BNF), hepatic aliesterases demonstrated lower specific activity; additionally, there was a reduced level of inhibition in BNF-pretreated rats following either parathion or paraoxon administration. However, any effects of BNF on parathion- or paraoxon-induced inhibition cannot be distinguished at this time from the effects of the oil vehicle, which reduced esterase inhibition, presumably by its ability to sequester the organophosphate. Brain acetylcholinesterase was partially inhibited before the hepatic aliesterases were maximally inhibited in all treatment groups. In most cases, plasma aliesterases were maximally inhibited within 15 min after organophosphate administration. Thus hepatic aliesterases constitute an important but not completely effective form of protection from the inhibitory effects of organophosphates.
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PMID:Time course of inhibition of acetylcholinesterase and aliesterases following parathion and paraoxon exposures in rats. 233 15

The present study examined the effects of a glucocorticoid and a mineralocorticoid on organophosphorus-induced delayed neuropathy (OPIDN) as previous investigations have indicated that an endogenous steroid with both properties could alter this syndrome in chickens. The glucocorticoid triamcinolone and the mineralocorticoid deoxycorticosterone were provided in the diet beginning 1 day before and continuing 10 days after triortho-tolyl phosphate (TOTP, 360 mg/kg po), phenyl saligenin phosphate (PSP, 2.5 mg/kg im), and diisopropyl phosphorofluoridate (DFP, 1 mg/kg sc). In a manner similar to that seen with corticosterone, a low concentration (0.1 ppm) of triamcinolone reduced and a high concentration (10 ppm) exacerbated clinical signs. Concentrations of deoxycorticosterone under 80 ppm also partially delayed or ameliorated ataxia induced by TOTP, PSP, and DFP, but a combination of 0.1 ppm triamcinolone and 80 ppm deoxycorticosterone was not more effective than triamcinolone alone. Peripheral nerve damage was noted in all chickens given organophosphorus compounds, whether or not they had been given corticoids. Both steroids induced hydroxylase activity, but effects on most other enzyme systems examined were unremarkable. High concentrations of triamcinolone (10 ppm) could, however, also reduce liver cytochrome P450 levels and liver cholinesterase activity. Exacerbation of OPIDN was most notable in chickens under highest stress, as indicated by elevated heterophil-to-lymphocyte ratios. The clinical, pathological, biochemical, and hematological indices of exposure to adrenocorticoids and agents inducing OPIDN in chickens were, therefore, similar for both a synthetic glucocorticoid and the endogenous steroid corticosterone.
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PMID:Types of adrenocorticoids and their effect on organophosphorus-induced delayed neuropathy in chickens. 334 Oct 34

Rats were treated, during 8 weeks, with different doses of edifenphos (0, 5, 10, 20, 40 mg/kg/day) incorporated in the food. Treatments with 20 and 40 mg/kg increased the relative liver weight and hepatic concentrations of phospholipids, microsomal proteins and cytochrome P450. Aminopyrine N-demethylase and aniline hydroxylase activities were increased at the same doses. Hepatic lipids and blood triacylglycerols remained unchanged by the treatment, but blood cholesterol increased significantly (33%) at 40 mg/kg. Plasma cholinesterase activity was slightly depressed in rats treated with the two higher doses. Under these experimental conditions, the dose of edifenphos, inducing no significant difference was 10 mg/kg/day.
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PMID:Biochemical changes in liver and plasma of rats after oral administration of edifenphos. 683 11

Phenobarbital and some other enzyme-inducers are known to reduce organophosphate toxicity. One suggested mechanism is the induction of liver cytochrome P450 enzymes catalyzing monooxygenation reactions. The aim of the present study was to elucidate the cytochrome P450 subfamily, or P450 isoenzyme(s), participating in the detoxification of diisopropyl fluorophosphate (DFP) in the rat. DFP resulted in a type I spectrum in liver microsomes from phenobarbital- or RP 52028-treated rats (binding constants 0.32 and 0.17 microM, respectively) and in a purified P450 preparation enriched with CYP2B. The spectrum was reversible by metyrapone, an inhibitor of the CYP2B enzyme subfamily. The 7-pentoxyresorufin O-dealkylase activity was inhibited by DFP in liver microsomes from phenobarbital- or RP 52028-treated rats and in a reconstituted system containing the purified CYP2B preparation. In microsomes from phenobarbital-pretreated rats, the inhibition was of a mixed type, i.e., competitive-non-competitive (Km = 0.5 microM; Ki = 6 microM). The microsomal fractions of livers from phenobarbital- or RP 52028-treated rats detoxified DFP effectively in vitro, as measured by a decrease in the DFP inhibition of cholinesterase activity. This detoxification was antagonized by metyrapone and by an antibody raised against purified CYP2B preparation. Clotrimazole, an inhibitor of P450 enzymes, inhibited the detoxification of DFP in rat liver in vivo. A genetically-modified hamster cell line expressing CYP2B1 oxidized NADPH in the presence of DFP. No such oxidation was detected in the parent cell line. These studies suggest that CYP2B1 metabolizes DFP and may significantly contribute to the detoxification of this organophosphate in vivo.
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PMID:P450 enzyme CYP2B catalyzes the detoxification of diisopropyl fluorophosphate. 782 Aug 84

The potential for toxic interactions between ergosterol biosynthesis-inhibiting fungicides (EBIFs), used in U.S. agriculture or clinically, and phosphorothioate insecticides was assessed in adult male rats and adult male bobwhite quail (Colinus virginianus) by measuring inhibition of plasma butyryl cholinesterase (BChE) following fungicide and insecticide treatment. Male Sprague-Dawley rats (300 g) were administered corn oil or the following EBIFs: propiconazole (400 mg/kg/day), vinclozolin (400 mg/kg/day), clotrimazole (100 mg/kg/day), or ketoconazole (100 mg/kg/day) for 3 days by oral gavage. Forty-eight hours following the final dose, a single bolus of parathion (0.4 mg/kg in corn oil) or malathion (150 mg/kg in corn oil) or corn oil alone was given po. The rats were terminated 12 hr following parathion or 4 hr following malathion dosing. Significant (p < 0.05) inhibition of BChE was observed with parathion and malathion only following clotrimazole treatment. In contrast, when a similar experiment was performed in bobwhite quail dosed with 12 mg/kg malathion following EBIF treatment, significant BChE inhibition was observed following treatment with vinclozolin or ketoconazole, but not with propiconazole or clotrimazole. Induction of cytochrome P450 in rat and quail liver by EBIFs was accompanied by enhanced oxidative desulfuration of malathion, parathion, and diazinon to toxic oxon products. Increased detoxication via oxidative dearylation/esterolytic clevage also occurred. However, while enhanced acute in vivo insecticide toxicity was observed in both species with a number of EBIF-phosphorothioate combinations, EBIF-induced oxidative activation of phosphorothioates by liver microsomes in vitro was not a good predictor of this effect.
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PMID:Toxic interactions between fungicides that inhibit ergosterol biosynthesis and phosphorothioate insecticides in the male rat and bobwhite quail (Colinus virginianus). 787 35

Guineapigs exposed to acute and subacute levels of toxaphene revealed a marginal reduction in the body weight. There was a significant inhibition of acetylcholinesterase and ATPases in the brain, liver and kidney. The effect of subacute toxicity of toxaphene resulted in an enhancement of cytochrome P450 and induction of aniline hydroxylase in liver and kidney. Biochemical investigations on the backbone revealed that toxaphene toxicity caused an increase in the calcium content and a decrease in the collagen content significantly. Toxaphene was accumulated more in the liver than in the kidney as reflected by residue studies.
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PMID:Effect of toxaphene toxicity on enzyme activity & residue levels in vital organs of guineapig. 826 81

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
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PMID:Metabolic polymorphisms. 836 90

Neuroblastoma cell lines were used to examine the differential interspecies response (i.e., species selectivity) to organophosphates (OPs). Baseline activities of the major target esterases, i.e., cholinesterase, carboxylesterase, and neurotoxic esterase, were assayed in mouse and several human neural candidate cell lines. These activities were found to be variable within individual cell lines and among the various tested cell lines. Cytotoxicity data using the neutral red fluorometric assay were collected on both human (SH-SY5Y) and mouse (NB41A3) neuroblastoma clones exposed to a variety of OP insecticides. IC50 data indicated that the tested mouse cell line was consistently more sensitive than the human cell line to equimolar doses of various OP compounds (e.g., mipafox, parathion, paraoxon, DFP, leptophos oxon, fenthion, and fenitrothion). This difference in cytotoxic sensitivity was most pronounced in response to compounds requiring metabolic bioactivation (i.e., protoxicants). Cytotoxicity data also demonstrated that the NB41A3 mouse neuroblastoma cell line was more metabolically competent than the SH-SY5Y human cell line in converting the protoxicant parathion to its neurotoxic metabolite, paraoxon. B-lymphoblastoids, genetically engineered with human P450 cDNAs, demonstrated higher cytotoxic sensitivity to parathion than unengineered cells, indicating that cytochrome P450-associated monooxidase activity could also influence cytotoxic sensitivity to parathion in culture. These data suggest that interspecies-selectivity in response to OP-related cytotoxicity is influenced by intercellular differences in metabolism and baseline esterase activities.
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PMID:Differential cytotoxic sensitivity in mouse and human cell lines exposed to organophosphate insecticides. 851 93

Comparison of published LD50 or LC50 levels for a variety of insecticides in several vertebrate species indicate that a wide range of toxicity levels exist, and these cannot be easily predicted within either a chemical group or within a species. There is a relatively limited data base documenting interactions between insecticides and other chemicals, either agricultural or non-agricultural; however, the fact that all major insecticide groups perturb nervous system function as their primary mechanism of acute toxicity suggests the potential for interactions. Studies in our laboratories on a select group of phosphorothionate insecticides in rats indicated that brain acetylcholinesterase sensitivity to inhibition by the oxons, the active metabolites of the phosphorothionates, does not correlate with acute toxicity levels. The activities and properties of hepatic cytochrome P450-mediated activation (desulfuration) and detoxication (dearylation) of the phosphorothionates as well as of A-esterase-mediated hydrolysis of oxons contribute substantially to understanding the acute toxicity levels in rats, as does the sensitivity of the protective aliesterases to phosphorylation. However, in the channel catfish, the acetylcholinesterase sensitivity to oxon inhibition reflects the acute toxicity level of these same insecticides, and may be largely responsible for determining the acute toxicity level in this species. Thus, metabolism of insecticides appears to be far more influential in some species than others in determining the toxicity elicited.
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PMID:Biochemical mechanisms contributing to species differences in insecticidal toxicity. 857 66


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