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)

Broad spectrum organophosphate resistance in Culex quinquefasciatus Say from Saudi Arabia is inherited as a semi-dominant characteristic. The resistance has a metabolic basis and confers cross-resistance against the carbamate propoxur. Organophosphate-selected strains contain two elevated esterases with the same electrophoretic mobilities as those in resistant Cx quinquefasciatus from Sri Lanka and a range of African locations. Alteration in the sensitivity of acetylcholinesterase to insecticide inhibition does not play a major role in resistance. There was a significant increase in the amount of Cytochrome P450 in Cx quinquefasciatus lines selected with the pyrethroid permethrin or with the organophosphate pirimiphos-methyl, but no change in lines selected with five other organophosphates or propoxur, compared to the parental strain, which suggests that oxidases are involved in the P450 mediated resistance to both permethrin and pirimiphos-methyl.
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PMID:Mechanisms of organophosphate and carbamate resistance in Culex quinquefasciatus from Saudi Arabia. 213 92

We have demonstrated that incubation of rat liver microsomes with N-hydroxy-2-acetylaminofluorene (N-OH-AAF) leads to formation of a 2-nitrosofluorene-membrane lipid adduct. This adduct exists as a nitroxyl free radical, termed N-O-LAF, in its oxidized state. When microsomes were incubated with the sulfhydryl binding agent, rho-hydroxymercuribenzoate, a larger amount of N-OL-LAF formed. We interpret this as a slowdown in the rate of endogenous chemical reduction of carcinogen-membrane lipid adduct. In this paper we present evidence that N-OH-AAF is deacetylated by a microsomal enzyme to form N-hydroxy-2-aminofluorene and this is then oxidized to 2-nitrosofluorene which adds covalently to membrane lipid double bonds to form N-O-LAF. Various antioxidants, peroxidase inhibitors, and P450 substrates and inhibitors were ineffective in altering the amount of N-O-LAF formed from N-OH-AAF; but two esterase inhibitors, dietyl-rho-nitrophenylphosphate and alpha-toluene-sulfonyl fluoride, prevented N-O-LAF formation. Of the following purified enzymes tested: porcine liver carboxyl esterase, pepsin, chymotrypsin, cathepsin D, ficin, papain, leucine aminopeptidase, Naja naja phospholipase, acetylcholinesterase (type I), trypsin (type I and V) and epoxide hydrase; only carboxyl esterase was effective in deacetylating N-OH-AAF.
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PMID:The deacetylation of N-hydroxy-2-acetylaminofluorene by rat liver microsomes and carboxyl esterase. 626 Mar 32

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

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

Evidence based on thermal lability and enzyme inhibition data suggests that the sulfoxidation of methiocarb (an N-methylcarbamate insecticide) by rat liver microsomes is catalyzed by flavin-containing monooxygenase(s) (FMO) and by cytochrome(s) P450 (P450). In control rats, the relative proportion is ca. 50% P450:50% FMO. Stereoselective formation of methiocarb sulfoxide from the corresponding sulfide has also been examined to compare the enantioselectivity of the two different enzyme systems. Only the FMO-dependent sulfoxidation presents a high stereoselectivity with an enantiomeric excess of 88% in favor of the (A)-enantiomer. Pretreatment of rats with different P450 inducers such as phenobarbital, 3-methylcholanthrene, dexamethasone, and pyrazole did not affect, or decreased, the rate of methiocarb sulfoxidation. Stereoselectivity of the reaction was modified, mainly because of changes in the relative involvement of FMO and P450 in sulfoxidase activity in pretreated animals. The acetylcholinesterase inhibition properties of methiocarb and its main metabolites were also investigated. Racemic methiocarb sulfoxide was slightly less inhibitory (Ki = 0.216 microM-1.min-1) than methiocarb, but a 10-fold difference was observed between the bimolecular rate constants found for the two sulfoxides produced (0.054 and 0.502 microM-1.min-1 for the (A) and (B) enantiomers, respectively).
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PMID:Stereoselective sulfoxidation of the pesticide methiocarb by flavin-containing monooxygenase and cytochrome P450-dependent monooxygenases of rat liver microsomes. Anticholinesterase activity of the two sulfoxide enantiomers. 856 32

Juvenile rats are more susceptible to the acute toxicity of the phosphorothionate insecticides parathion and chlorpyrifos than are adult rats. Developmental changes in brain acetylcholinesterase and hepatic aliesterase (carboxylesterase), cytochrome P450, and the P450-mediated metabolism of these two phosphorothionate insecticides were investigated in male Sprague-Dawley rats. Specific activities of acetylcholinesterase in cerebral cortex, but not medulla oblongata, and of liver aliesterases increased with age, indicating the presence of both more target esterases and more protective esterases, respectively, in the adult compared to the juvenile animal. Sensitivity of the brain acetylcholinesterase to inhibition by paraoxon and chlorpyrifosoxon, as measured by IC50 values, did not change significantly with age, whereas the hepatic aliesterase sensitivity to inhibition decreased with age. Progressive increases in activities of P450-mediated activation (desulfuration) (6- to 14-fold) and detoxication (dearylation) (2- to 4-fold), as well as concentrations of P450 (7-fold) and protein (2-fold), were observed between neonate and adult hepatic microsomes. Microsomal pentoxyresorufin O-dealkylase activity followed a developmental pattern similar to desulfuration and dearylation, displaying a 16-fold increase between neonates and adults. However, microsomal ethoxyresorufin O-deethylase activity increased until 21 days of age, displaying a 16-fold increase, then decreased in adulthood to a level 10-fold higher than neonates. These results indicate that target enzyme sensitivity is not responsible for age-related toxicity differences, nor is the potential for hepatic bioactivation, whereas lower levels of hepatic aliesterase-mediated protection and P450-mediated dearylation probably contribute significantly to the greater sensitivity of juveniles to phosphorothionate toxicity.
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PMID:Age-related differences in parathion and chlorpyrifos toxicity in male rats: target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism. 943 36

The majority of insecticides currently in use throughout the world belong to the class of the organophosphorus insecticides. Many of these compounds, such as the phosphorothioate insecticides, exert their mammalian toxicity only after undergoing metabolic activation by a variety of cytochrome P450 isoforms to produce their corresponding oxygen analogs (or oxons), which are potent inhibitors of the critical enzyme acetylcholinesterase. Of the many chemicals identified that can modulate cytochrome P450-dependent activities, the flavonoids represent some of the most unusual compounds in that they have been reported to both inhibit and stimulate certain activities. The present study was undertaken to determine if representative flavonoids (at in vitro concentrations of 1-100 microM) can alter the mammalian cytochrome P450-dependent biotransformation and acute toxicity of the phosphorothioate insecticide parathion. The flavonoids 5,6-benzoflavone, flavone, and quercetin had the biphasic effect of stimulating mouse hepatic microsomal parathion oxidation at a concentration of 1 microM, and inhibiting this same activity when increased to 100 microM. In contrast, 7,8-benzoflavone was only inhibitory at all concentrations examined. All the flavonoids examined except quercetin altered the ratio of activation/detoxification of parathion by mouse hepatic microsomes, but had no effect on this same ratio with human CYP1A2. These data suggest that the changes in the activation/detoxification ratio observed with mouse hepatic microsomes resulted from selective inhibition or stimulation of various cytochrome P450 isoforms rather than a flavonoid-induced alteration in the nonenzymatic rearrangement of the putative phosphooxythirane intermediate generated by cytochromes P450 from parathion. Surprisingly, however, none of the four flavonoids in the current study affected the lethality of parathion in vivo, suggesting that the flavonoid-induced alterations in cytochrome P-450-dependent metabolism of parathion documented in vitro were simply not great enough to be of any significance in vivo.
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PMID:Flavonoid-induced alterations in cytochrome P450-dependent biotransformation of the organophosphorus insecticide parathion in the mouse. 992 30

Cytochrome P450 monooxygenase system and acetylcholinesterase (AChE) activity were studied in the red swamp crayfish Procambarus clarkii sampled from the Ebro Delta before and after spraying of the area with fenitrothion. Analysis of hepatopancreas microsomes revealed an increase of 7-ethoxyresorufin O-deethylase (EROD) activity in organisms sampled after spraying. AChE activity was significantly inhibited in the same specimens, corroborating that these organisms were exposed to fenitrothion, and the usefulness of AChE as a marker of pesticide poisoning in P. clarkii. Crayfish from a reference site were analyzed and the results compared with those obtained in organisms from the Ebro Delta. The ability of P. clarkii to metabolize the organophosphorus pesticide fenitrothion was determined in vitro by using microsomal fractions isolated from hepatopancreas. The results pointed out the existence of an oxidative metabolism, which was inhibited by different P450 inhibitors (clotrimazole, alpha-naphthoflavone and N-benzylimidazole) and not affected by methimazole.
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PMID:Cytochrome P450 system in the hepatopancreas of the red swamp crayfish Procambarus clarkii: a field study. 997 75

In human populations, serum paraoxonase (PON1) exhibits a substrate dependent polymorphism. The Arg192 isoform hydrolyzes paraoxon rapidly but diazoxon, soman and especially sarin slowly. On the other hand, the Gln192 isoform hydrolyzes paraoxon slowly, but diazoxon, soman and sarin more rapidly than the Arg192 isoform. Our experiments with a mouse model system have convincingly shown that PON1 plays a major role in the detoxication of organophosphate (OP) compounds processed through the P450/PON1 pathway. Recent studies have also shown that PON1 plays an important role in the metabolism of oxidized lipid compounds. Currently, there is an effort underway to identify genes and polymorphisms that play an important role in 'environmental susceptibility'. The PON1 polymorphism has been cited as a prime example of such a genetic polymorphism. The advent of the polymerase chain reaction (PCR) for DNA amplification with improvements, modifications and automation has provided a very convenient way to do individual genotyping. It is tempting to set up large scale PCR analyses of populations to determine individuals at risk for environmental exposures affected by the PON1 polymorphism. In fact, a number of such studies have already been carried out in examining the relationship of the PON1 polymorphism to vascular disease. We advocate the use of a high throughput two-dimensional enzyme assay that provides both PON1 genotype and phenotype (PON1 status). The high level of variation of gene expression within each genetic class in humans, together with our animal model studies indicate that it is very important to determine PON status as opposed to PON1 genotype alone. Experiments in rats and mice have shown that injection of PON1 purified from rabbit serum by the i.v., i.p. or i.m. route, significantly increases PON1 activities in rodents' plasma. Under these conditions, the acute toxicity (assessed by the degree of acetylcholinesterase inhibition) of paraoxon and chlorpyrifos oxon is significantly decreased, compared to control animals. Protection is maximal when PON1 is administered before the OPs, but still occurs when PON1 is utilized as a post-exposure treatment. Furthermore, protection by PON1 is also provided toward the parent compound chlorpyrifos. Pon1-knockout mice display a much greater sensitivity to chlorpyrifos oxon toxicity than wild mice. However, the acute toxicity of guthion, which is not a substrate for PON1, does not differ between knockout and wild mice. These observations underline the importance of considering both genetic variability of enzyme isoform as well as enzyme level (PON1 status) and the developmental time course of appearance of PON1 in developing risk assessment models.
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PMID:The role of paraoxonase (PON1) in the detoxication of organophosphates and its human polymorphism. 1042 80


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