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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorpyrifos (CPF), a commonly used cholinesterase-inhibiting insecticide, is lethal at much lower doses to young animals than adults. To explain this higher sensitivity in younger animals, we hypothesized that young rats have less chlorpyrifos-oxonase (CPFOase) activity than adults. To test this hypothesis, CPFOase activity was measured in the brain, plasma, and liver of male, postnatal day 4 (PND4) and adult (PND90) Long-Evans rats. CPFOase is biochemically defined as a Ca(2+)-dependent A-esterase that hydrolyzes chlorpyrifos-oxon (CPFO), the active metabolite of CPE. No brain CPFOase activity was detected at either age. Plasma and liver CPFOase activities were markedly lower at PND4 compared to adult: PND4 plasma and liver CPFOase activities were 1/11 and 1/2 the adult plasma and liver activities, respectively. Because the Km of CPFOase activity was high (i.e., 210-380 microM), it was important to determine if this CPFOase activity could hydrolyze physiologically relevant concentrations (i.e., nM to low microM) of CPFO. This was accomplished by comparing the shifts in the tissue acetylcholinesterase (AChE) IC50 for CPFO in the presence or absence of CPFOase activity. One would expect an increase in the "apparent" IC50 if CPFOase hydrolyzes substantial amounts of CPFO during the 30 minutes the tissue is preincubated with the CPFO. In the adult, both plasma and liver AChE apparent IC50 values were higher in the presence of CPFOase activity, suggesting that the CPFOase in those tissues was capable of hydrolyzing physiologically relevant concentrations of CPFO within 30 minutes. In young animals, however, there was less of a shift in the IC50 curves compared to the adult, confirming that the young animal has less capacity than the adult to detoxify physiologically relevant concentrations of CPFO via CPFOase.
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PMID:Maturational differences in chlorpyrifos-oxonase activity may contribute to age-related sensitivity to chlorpyrifos. 926 78

Chlorpyrifos (CPF) is a cholinesterase-inhibiting organophosphate pesticide used extensively to treat crops and domestic animals. Two experiments determined the effects of acute and repeated CPF exposure on the acquisition and performance of response sequences. Adult male Long-Evans rats (n = 16), maintained at 300 g body weight were trained using food reinforcement under a multiple schedule of repeated acquisition (RA) and performance (P). The RA component required completion of a four-response sequence on three levers (e.g., center, right, left, right) that changed with each session, while the correct sequence in the P component was invariant. In experiment I, rats were orally administered vehicle (corn oil), 12.5, 25, 37.5 and 50 mg/kg CPF. Doses of 37.5 and 50 mg/kg produced greater accuracy decreases in RA than in P, suggesting a selective learning deficit. In experiment II, the rats were divided into two groups (n = 7), and received either vehicle or 12.5 mg/kg CPF, 5 day/wk, for 8 wk. Although 12.5 mg/kg CPF was barely effective when administered acutely, when administered repeatedly it initially decreased accuracy in both RA and P. Tolerance developed to CPF effects on P accuracy but not on RA accuracy. Microanalyses of response patterns indicated the most common type of error was a progression through the sequence as if incorrect responses were actually correct. Radiometric analyses of serum cholinesterase activity showed CPF produced 90% inhibition at 3 hr and 85% inhibition at 24 hr postexposure. These results show that both acute and repeated CPF produced a selective deficit in the learning of response sequences in rats. This selectivity was most clearly expressed through the development of tolerance to the disruptive effects of repeated CPF on the performance but not the learning of response sequences.
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PMID:Chlorpyrifos produces selective learning deficits in rats working under a schedule of repeated acquisition and performance. 933 38

Young rats are more sensitive than adults to a single oral dose of chlorpyrifos, an organophosphorus pesticide. A direct comparison of chlorpyrifos effects in young (postnatal day 17; PND17), adolescent (PND27), and adult (70 days) Long-Evans rats was conducted to determine quantitative and possibly qualitative differences in sensitivity in terms of behavioral changes and cholinesterase (ChE; total cholinesterase activity) inhibition at these three ages. Male and female rats were administered chlorpyrifos orally at one of two doses (PND17, 5 or 20 mg/kg; PND27, 20 or 50 mg/kg; adult, 20 or 80 mg/kg) and tested at either 3.5 or 6.5 h after dosing. Behavioral testing included observational evaluations and measurements of motor activity and was followed immediately by tissue collection for ChE determination in brain and blood. For both behavioral changes and ChE inhibition, peak effects occurred at 3.5 h in adult male and PND27 rats (both sexes) and at 6.5 h in adult female and PND17 rats (both sexes). Comparisons of the 20 mg/kg dose across ages showed generally less ChE inhibition and fewer behavioral effects with increasing age, except that the adult females were similar to the PND27 rats. The high dose used for each age group produced similar brain ChE inhibition (80-90%) and generally similar behavioral effects. Interestingly, a few end-points in the young rats were less affected than in adults at this level of ChE inhibition. The degree of ChE inhibition in the brain more closely paralleled the blood inhibition in the younger rats, compared to the adults. Carboxylesterase (CaE) and A-esterase are known to play an important role in the detoxification of organophosphates and may be partially responsible for these sensitivity differences. Liver and plasma CaE and A-esterase activities were measured in untreated male rats on PND1, 4, 7, 12, 17, and 21 and in adults of both sexes (82-92 days old). Preweanling rats had considerably less activity of both enzymes, and adult females had less liver CaE activity than males. These differences in detoxifying enzymes correlate with the age-related differences in behavioral and biochemical effects, as well as the gender differences seen in adult rats, and thus may be a major influence on the differential sensitivity to chlorpyrifos.
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PMID:Age- and gender-related differences in sensitivity to chlorpyrifos in the rat reflect developmental profiles of esterase activities. 1004 24

Chlorpyrifos (O,O'-diethyl O-[3,5,6-trichloro-2-pyridyl] phosphorothionate) is a commonly used anticholinesterase insecticide, and therefore the potential for human exposure is high. The present time course and dose response studies were conducted to delineate the toxicokinetics of chlorpyrifos and its metabolites in the pregnant rat and fetus. Time-pregnant, Long-Evans rats were treated orally with chlorpyrifos during late gestation (Gestational Days 14-18). Following euthanasia the level of chlorpyrifos and its metabolites, chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol (TCP), were measured in both fetal and maternal brain and liver (limits of quantitation: 59.2, 28.8, and 14.0 ng/g tissue, respectively). In addition, cholinesterase inhibition was also measured in the same tissues for comparison. TCP was the only component detected. The highest level of TCP and the lowest level of cholinesterase activity showed the same time of peak effect: 5 h after the last dose. The concentration of TCP in the maternal liver was approximately fivefold higher than the TCP concentration in fetal liver, but, paradoxically, the concentration of TCP in the fetal brain was two- to fourfold higher than the TCP concentration in the maternal brain. The half-life of the TCP was identical in all tissues examined (12-15 h). These toxicokinetic results suggest that the fetal nervous system may be exposed to a higher concentration of chlorpyrifos than the maternal nervous system when the dam is orally exposed to chlorpyrifos during late gestation.
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PMID:Gestational exposure to chlorpyrifos: comparative distribution of trichloropyridinol in the fetus and dam. 1038 28

Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic response followed by a delayed fever. Fever from infection is mediated by the release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF alpha). This study determined if the CHP-induced fever involves cytokine-mediated mechanisms similar to that of infectious fevers. Long-Evans rats were gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized and blood collected at various times that corresponded with the hypothermic and febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE), total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE activity was reduced by approximately 50% 4 h after CHP. There was no effect of CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever. TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The changes in plasma cytokine levels following CHP were relatively small when compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data suggest that the delayed fever from CHP is unique, involving mechanisms other than TNF alpha and IL-6 release into the circulation characteristic of infectious fevers.
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PMID:Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever? 1041 84

Female Long-Evans rats were gavaged 5 days a week for 4 weeks with chlorpyrifos in oil at dosages of 0, 1, 3, and 10 mg/kg/day. Clinical observations were conducted, and memory was tested with a delayed matching-to-position task (DMTP). Before exposure started, the rats were divided into four groups of ten of comparable overall performance. Then, they were tested during four weeks of dosing and for another four weeks thereafter. The observer was not provided information about each rat's dose group identification. Miosis was a prominent sign observed in the 3 and 10 mg/kg/day groups. Rectal temperature was reduced in the 10 mg/kg/day group. Noncognitive performance measures in the DMTP test (e.g., actual total delay, void trials) were affected and consistent with decreased motor activity. There was a statistically significant difference in the intercept at the zero delay (i.e., a measure of encoding/motivation/attention), which was attributed to deviations from controls in the high-dosage group during dosing weeks 2 and 3 (in opposite directions). This difference was not considered treatment related. The slope of the retention gradient (i.e., a measure of forgetting rate) did not show any statistically significant difference between groups at dosages that inhibited brain cholinesterase by up to approximately 85%. In conclusion, chlorpyrifos decreased motor activity but had no effects on short-term memory (i.e., information retention capability) and on encoding/motivation/attention.
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PMID:Chlorpyrifos: lack of cognitive effects in adult Long-Evans rats. 1075 53

It is often assumed that cognitive function is more sensitive to neurotoxic chemicals than are the unconditioned behaviors employed in neurobehavioral screens; however, direct comparisons of the sensitivity of these test methods are lacking. The present studies were conducted to compare the effects of the widely used cholinesterase-inhibiting insecticide, chlorpyrifos (O,O'-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), on a visual signal detection task (SDT) with its effects on a neurobehavioral test battery. Adult male Long-Evans rats were trained to perform the SDT, dosed with CPF, and then assessed with both test instruments. Oral CPF (50 mg/kg) impaired signal detection for 8 days, and subcutaneous CPF (250 mg/kg) did so for 4 weeks. CPF (30 and 50 mg/kg po and 250 mg/kg sc) also lowered activity in the test battery for up to 18 days. Thus, CPF impaired attention and altered behavior in the test battery in the same dose ranges under two very different dosing scenarios.
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PMID:Comparing cognitive and screening tests for neurotoxicity. Effects of acute chlorpyrifos on visual signal detection and a neurobehavioral test battery in rats. 1127 74

After an acute (4 h) treatment with an irreversible cholinesterase inhibitor organophosphate, metrifonate (100 mg/kg i.p.), the activities of both acetyl- and butyrylcholinesterase were inhibited (66.0-70.7% of the control level) in the rat brain cortex and hippocampus. There were no significant changes in the acetyl- and butyrylcholinesterase activities in the olfactory bulb, or in the choline acetyltransferase activity in all three brain areas. After chronic (2 or 5 week) metrifonate treatment (100 mg/kg daily i.p.), the activities of both cholinesterases were substantially inhibited in the rat brain cortex and hippocampus (15.8-31.8% of the control levels), but there was no inhibition of the choline acetyltransferase activity. Moreover, chronic metrifonate treatment did not have any effect on the distribution of the acetylcholinesterase molecular forms. In vitro, metrifonate proved to be a more potent inhibitor of butyryl- than of acetylcholinesterase in both the cortex and the hippocampus. In the hippocampus, the butyrylcholinesterase activity was twice as sensitive to metrifonate inhibition as that in the cortex (IC50 values 0.22 and 0.46 microM, respectively). The effects of chronic (5 week) metrifonate treatment on the blood-brain barrier of the adult rat were examined. The damage to the blood-brain barrier was judged by the extravasation of Evans' blue dye in three brain regions: the cerebral cortex, the hippocampus, and the striatum. No extravasation of Evans' blue dye was found in the brain by fluorometric quantitation. These data indicate that chronic metrifonate treatment may increase the extracellular acetylcholine level via cholinesterase inhibition, but it does not have any effects on the blood-brain barrier. Therefore, it appears reasonable to hypothesize that cholinesterase activities do not play a role in the blood-brain barrier permeability.
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PMID:Effects of chronic metrifonate treatment on cholinergic enzymes and the blood-brain barrier. 1131 45

Previous studies have shown that moderate to high levels of chlorpyrifos (CPF) alter cognitive function in adult and immature rats. In the present study, we tested the hypothesis that lower-level exposure to CPF before or immediately after weaning causes deficits in cognitive function. A total of 78 Long-Evans rats were injected subcutaneously with 0, 0.3 or 7.0 mg/kg CPF every 4 days before or after weaning and were tested with the Morris swim task from postnatal day 24 through 28. Exposure to CPF before weaning did not cause signs of overt cholinergic intoxication or impaired growth nor did the exposures cause significant inhibition of regional brain cholinesterase (ChE) activity or reduction in muscarinic receptors 24 h after the last injection. However, spatial learning was impaired after 5 days of training in the group of weanling rats administered 7.0 mg/kg CPF. Rats administered 0.3 or 7.0 mg/kg CPF after weaning were also impaired in the task, without significant changes in brain ChE activity. These data indicate that low-level exposure to CPF caused deficits in cognitive function in weanling rats, and these effects did not appear to be mediated by the inhibition of brain ChE. It is suggested that the alteration of cognitive function in juvenile rats is an important functional correlate of the cellular and molecular effects of CPF in the immature brain. The mechanisms for CPF-induced cognitive dysfunction are unknown.
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PMID:Cognitive function and cholinergic neurochemistry in weanling rats exposed to chlorpyrifos. 1144 24

Diazinon is an organophosphate (OP)-based, anticholinesterase insecticide that irreversibly inhibits acetylcholinesterase activity and produces cholinergic stimulation in central nervous system (CNS) and peripheral tissues. Our laboratory has found that OPs administered orally in rats induce a transient period of hypothermia followed by a delayed fever that persists for several days after exposure. There is little information on the thermoregulatory effects of diazinon. Core temperature (Tc) and motor activity (MA) were monitored by radiotelemetry in male and female rats of the Long-Evans strain dosed orally with diazinon (0 [corn-oil vehicle], 100, 200, or 300 mg/kg in males and 0, 50, 100, or 200 mg/kg in females). There was a dose-dependent decrease in Tc during the first night after treatment, with females exhibiting slightly greater sensitivity than males. MA was unaffected in females exposed to diazinon at doses of 50 to 200 mg/kg; MA of males was reduced during the first night after dosing with 300 mg/kg. There was a delayed elevation in Tc of males dosed with 200 and 300 mg/kg and females dosed with 50, 100, and 200 mg/kg diazinon. The elevated Tc was only manifested during d 2 and 3 after diazinon. Administration of 200 mg/kg sodium salicylate to females 48 h after being treated with 200 mg/kg diazinon led to a rapid abatement of the fever. Diazinon doses of 50 to 300 mg/kg led to 40% to 50% inhibition in plasma cholinesterase (ChE) activity 4 h after dosing, and females displayed a significantly slower recovery of ChE activity compared to males. When compared on a molar basis, the hypothermic response to diazinon was relatively small compared to other OPs such as chlorpyrifos. The delayed fever and efficacy of sodium salicylate to block diazinon-induced fever are similar to the effects of OPs chlorpyrifos and diisopropyl fluoro-phosphate (DFP).
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PMID:Influence of gender on thermoregulation and cholinesterase inhibition in the long-evans rat exposed to diazinon. 1252 73


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