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)

Perfusion of mouse livers in situ with the phosphorodithioate pesticide azinphos-methyl (O,O-dimethyl S-[4-oxo-1,2,3-benzotriazin-3(4H)-ylmethyl] phosphorodithioate; Guthion) resulted in the appearance of the cholinesterase inhibitor azinphos-methyl oxon in effluent perfusate. Since mouse whole blood did not have the capacity to detoxify this toxic oxon rapidly enough to prevent its passage to extrahepatic tissues in vivo, the liver is likely a major source of azinphos-methyl oxon in the mouse following exposure to azinphos-methyl. Alterations in perfusate flow rates in situ had little effect on the hepatic disposition of azinphos-methyl. Conversely, significant increases in the free fraction of azinphos-methyl in perfusate led to marked changes in hepatic distribution and biotransformation of this pesticide. Phenobarbital pretreatment of mice induced hepatic cytochrome P-450 content, as well as microsomal activation of azinphos-methyl in vitro, yet antagonized the acute toxicity of this pesticide in vivo. Interestingly, perfused livers from phenobarbital-pretreated mice produced less azinphos-methyl oxon than perfused livers from saline-pretreated mice, thereby accounting for the antagonism of the acute toxicity of azinphos-methyl afforded by phenobarbital pretreatment. The mechanism of this phenobarbital-dependent decrease in appearance of azinphos-methyl oxon in effluent perfusate is unclear. However, it must be emphasized that the hepatic biotransformation of azinphos-methyl is complex, involving several sequential and simultaneous pathways, all of which could be affected by phenobarbital. The metabolic profile observed in effluent perfusate is the net result of all these pathways operating in the intact liver.
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PMID:Metabolic activation of the pesticide azinphos-methyl by perfused mouse livers. 362 98

Single-pass perfusion of mouse livers in situ with the phosphorothioate pesticide parathion resulted in formation of the cholinesterase inhibitor paraoxon (PO), p-nitrophenol (PNP), p-nitrophenyl sulfate (PNPS), and p-nitrophenyl glucuronide (PNPG). Daily pretreatment of mice with phenobarbital (80 mg/kg, ip) for 4 days induced hepatic cytochrome P-450 content, as well as oxidative activation and oxidative detoxification of parathion, as measured in vitro. However, phenobarbital pretreatment did not alter production of PO from parathion in mouse livers perfused in situ, although it increased production of PNP, PNPS, and PNPG. Additionally, phenobarbital pretreatment antagonized the acute toxicity of parathion in mice. These results indicate that phenobarbital pretreatment clearly induces that form(s) of cytochrome P-450 catalyzing conversion of parathion to PO. Yet increased amounts of PO do not exit perfused livers from phenobarbital pretreated mice. Instead, the enhanced detoxification of parathion to PNP, PNPS, and PNPG likely results in the observed antagonism of parathion's acute toxicity.
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PMID:The effects of phenobarbital pretreatment on the metabolism and acute toxicity of the pesticide parathion in the mouse. 376 30

5 cytochrome P-450 isozymes were purified from the livers of uninduced mice and reconstituted with purified NADPH cytochrome P-450 reductase and phospholipid. The pesticides parathion, fonofos, DEF, Mocap and profenofos were oxidized by the reconstituted monooxygenase system to form acetylcholinesterase (AChE) inhibitors. The bioactivation varied with the pesticide substrate and the cytochrome P-450 isozyme. Aldrin epoxidation occurred with all 5 isozymes, with cytochrome P-450 A1 being the most active. All fraction metabolized the pesticide synergist piperonyl butoxide (PBO) to form an inhibitory cytochrome P-450-PBO-metabolite complex. The reduced complex produced a spectrum in the Soret region which was characteristic for each of the cytochrome P-450 isozymes. Inhibition of aldrin epoxidation by PBO was found to be unrelated to the nature of the Soret spectrum.
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PMID:Oxidation of pesticides by purified cytochrome P-450 isozymes from mouse liver. 398 73

The sensitivity of the mouse to organophosphorus-induced delayed neurotoxicity (OPIDN) has been investigated. One group of five mice received two single 1000-mg/kg po doses of tri-o-cresyl phosphate (TOCP) at a 21-day interval (on Days 1 and 21 of the study); a second group of five mice was given 225 mg/kg of TOCP daily for 270 days. A third group of five animals served as an untreated control. All animals were killed 270 days after the start of the experiment. Daily po dosing of 225 mg/kg TOCP caused a decrease in body weight gain, muscle wasting, weakness, and ataxia which progressed to severe hindlimb paralysis at termination. On the other hand, po administration of two single 1000-mg/kg doses of TOCP at a 21-day interval produced no observable adverse effects. Brain acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activity were 35 and 10% of the control, respectively, in daily dosed animals while AChE and NTE in mice receiving two single 1000-mg/kg doses of TOCP were not significantly altered from the control group. Plasma butyrylcholinesterase activity was 12% of the control group in daily dosed animals. Hepatic microsomal enzyme activities of aniline hydroxylase and p-chloro-N-methylaniline demethylase and NADPH-cytochrome P-450 content in daily dosed animals were increased (141 to 161% of the control group) when compared to controls and mice receiving two single 1000-mg/kg doses of TOCP; the latter being not significantly different from each other. Degeneration of the axon and myelin of the spinal cord and sciatic fascicle were observed and were consistent with OPIDN. This study demonstrates that chronic dosing of TOCP produces OPIDN and induces hepatic microsomal enzyme activity in mice. It is concluded that while the mouse is susceptible to OPIDN, it is a less sensitive and a less appropriate test animal for studying this effect when compared to the adult hen.
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PMID:Characterization of delayed neurotoxicity in the mouse following chronic oral administration of tri-o-cresyl phosphate. 404 9

Male Wistar rats exposed to 50, 100 or 300 ppm methyl tertiary-butyl ether vapour for 2-15 weeks, 6 h daily, 5 days a week, showed a dose-dependent blood ether concentration after 2 weeks' exposure. Blood concentrations of tertiary-butanol, were also dose dependent indicating metabolic breakdown of the ether in vivo. The blood ether concentrations decreased after 6 weeks of exposure at the 50 ppm dose level and remained unaffected at higher doses while tertiary-butanol concentrations increased after 6 weeks with all doses, and began to decrease thereafter. Exposure caused a transient increase in UDP-glucuronosyltransferase activities in liver and kidney microsomes, almost no effects on hepatic cytochrome P-450 concentrations and a minor induction of kidney microsomal cytochrome P-450 content. Exposure produced almost no effect on brain succinate dehydrogenase, creatine kinase or acetylcholinesterase activities, while early inhibition of muscle creatine kinase activity was noted, accompanied by increased activity at the end of exposure.
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PMID:Biochemical effects of methyl tertiary-butyl ether in extended vapour exposure of rats. 409 53

The mean level of PCB residues in the liver of the Caspian turtle collected in nature was 23 ppm, or approximately 20-fold greater than that detected in the two bird species tested. Treatment of the turtles with aroclor 1254 resulted in a 30-fold increase in the level of PCB residues in the liver but did not cause any increase in the content of cytochrome P-450 and the desulfurase activity of this hemoprotein. The Ki value for acetylcholinesterase inhibition by paraoxon in brain homogenate of the Caspain terrapin was 3 and 2 orders of magnitude higher than that found in the African bulbul and the barn owl, respectively.
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PMID:Metabolism of parathion and brain cholinesterase inhibition in aroclor 1254-treated and untreated Caspian terrapin (Mauremys caspica rivulata, Emydidae, Chelonia) in comparison with two species of wild birds. 613 7

A single i.p. dose (120 mg/kg) of thiram given to male Sprague-Dawley rats caused a significant increase in the activity of SGOT and SGPT 24 hr post-treatment indicating liver damage. A considerable diminution in the serum cholinesterase activity was also noted in the treated rats as against the control animals. Additional evidence for thiram-induced liver toxicity is provided by the observation that there was approximately 50% inhibition of the activity of hepatic microsomal benzphetamine N-demethylase with a concomitant decrease in the concentration of cytochrome P-450, an important component of the mixed-function oxidase system. Although not significant, hepatic glutathione levels were also depleted by thiram, probably making the liver susceptible to toxic injury.
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PMID:Thiram-induced toxic liver injury in male Sprague-Dawley rats. 652 Mar 39

Growing male rats that weighed 120 +/- 5 g were kept for 30 days on the following synthetic diets: high protein diet (HPD), 59% casein; high fat diet (HFD), 50% saturated fat; and normal diet (ND), 19% casein, 10% saturated fat, and 60% sucrose. Other essential dietary ingredients were included in all the diets. All animals were injected at the end of the 30-day period with parathion [10 mg/kg intraperitoneal (ip) injection as a single dose] or dichlorvos (30 mg/kg ip as a single dose) to compare the effect of dietary pretreatments on mortality from parathion and dichlorvos. A lower dose of parathion (7.5 mg/kg) and dichlorvos (20 mg/kg) was employed in another set of experiments to compare the spontaneous regeneration of plasma and red blood cell (RBC) cholinesterase (ChE) activity at 2 hr, 1 day, 3 days, and 5 days after administration of parathion or dichlorvos. The effect of these diets on hepatic microsomal oxidases was also determined. Results showed that diets per se did not affect initial plasma and RBC ChE activity. The HPD and HFD significantly protected against mortality from parathion but not from dichlorvos. Hepatic microsomal cytochrome P-450 and aminopyrine demethylase activity were unchanged, but aniline hydroxylase activity was increased significantly by HPD and HFD. Parathion oxidase in hepatic microsomes was significantly increased in rats fed HFD only. For the HPD, spontaneous regeneration of ChE diminished in RBCs in parathion-intoxicated rats and in plasma and RBCs of dichlorvos-intoxicated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of high-fat and high-protein diets on toxicity of parathion and dichlorvos. 652 63

The principal biochemical mechanisms of resistance to insecticides involve either modified, less sensitive cholinesterase, esterase action, glutathione S-transferase action or cytochrome P-450-dependent monooxygenation. Both quantitative and qualitative differences in cytochrome P-450 isozymes are under genetic control and both are related to resistance. Recent characterization studies involving ligand binding and multiplicity of isozymes in Musca domestica (the housefly) are discussed in relation to resistance. The recent demonstration that multiple isozymes of glutathione S-transferase exist in susceptible and resistant insects is of interest, and some re-examination of their role in the mechanism of resistance is required. Esterases are a heterogeneous group of enzymes whose role in resistance has often been suggested but seldom rigorously defined. Purification studies in the green rice leafhopper, Nephotettix cincticeps, have involved an enzyme with carboxylesterase, phosphotriesterase and pyrethroid esterase activities. A similar enzyme, but without pyrethroid esterase activity, is also found in the housefly. In resistance such enzymes may serve either to catalyse hydrolysis or as binding proteins. It has been suggested, from time to time, that regulator genes, enzyme induction and gene magnification all play a part in controlling biochemical mechanisms of resistance, although clearly defined evidence has not always been brought forward. These hypotheses are re-examined.
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PMID:Biochemical mechanisms of resistance to insecticides. 655 14

The differential effects of oral and dermal administration of single doses of 100 to 1000 mg/kg S,S,S-tri-n-butyl phosphorotrithioate (DEF) on nonspecific esterases and liver metabolism enzymes were investigated one day following administration. O,O-Diethyl O-(4-nitrophenyl) phosphorothioate (parathion) and tri-o-cresyl phosphate (TOCP) were used as negative and positive controls for organophosphorus-induced delayed neurotoxicity (OPIDN). Brain acetylcholinesterase was significantly inhibited with topical doses of 500 and 1,000 mg/kg of DEF and with orally and dermally applied parathion. Plasma cholinesterase and liver microsomal carboxylesterase activities were significantly reduced from control in all treatment groups. Neurotoxic esterase (NTE) was significantly decreased from control with topical dosing of 200, 500, and 1000 mg/kg DEF and with TOCP treatments. Oral doses of DEF increased cytochrome P-450 content by 70 to 200% while dermal application caused a 200 to 325% increase over control. p-Chloro-N-methylaniline demethylase was also increased by DEF treatments but to a lesser extent than that of aniline hydroxylase or cytochrome P-450 content. TOCP and parathion had no significant effect on liver microsomal oxidative enzymes. Liver microsomal proteins from hens treated with phenobarbital (PB), 3-methylcholanthrene (3MC), or DEF were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A striking increase in a 49K protein band in microsomes from PB and DEF (616 and 338%, respectively) treated hens was seen, while the 55K protein band showed an 861% increase in microsomes from 3MC-treated hens. In conclusion, dermally applied DEF was more effective in inhibiting esterases and inducing cytochrome P-450 than orally administered DEF; toxicity was directly related to the dose and route of administration.
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PMID:Induction of hepatic microsomal cytochrome P-450 and inhibition of brain, liver, and plasma esterases by an acute dose of S,S,S-tri-n-butyl phosphorotrithioate (DEF) in the adult hen. 671 May 30


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