Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA or anandamide) play vital roles during nervous system development including regulating axonal guidance and synaptogenesis. The enzymatic degradation of 2-AG and AEA is highly susceptible to inhibition by organophosphate compounds in vitro. Furthermore, acute in vivo exposure of adult animals to the agricultural insecticide chlorpyrifos (CPS) caused moderate inhibition of both 2-AG and AEA hydrolysis. However, the effects of repeated exposure to lower levels of CPS, especially during development, on endocannabinoid metabolism in the brain is not known. To examine this, rat pups were orally exposed daily from postnatal days 10-16 to either 1.0, 2.5, or 5.0 mg/kg CPS. Body weight gain was reduced by 5.0 mg/kg on all days of treatment whereas 2.5 mg/kg reduced the weight gain only on the last two days of treatment. At 4-h postexposure on day 16, forebrain cholinesterase (ChE) activity and hydrolysis of 2-AG and AEA were inhibited in a dose-related manner, and the extent of inhibition from highest to lowest level was AEA hydrolysis > ChE activity > 2-AG hydrolysis. The extent of inhibition of AEA hydrolysis was approximately twice than that of ChE activity with AEA hydrolysis being virtually eliminated by 2.5 and 5.0 mg/kg and 1.0 mg/kg causing 40% inhibition. The sensitivity of AEA hydrolysis, compared with canonical targets such as ChE activity, suggests a potential alternative developmental target for CPS. Inhibition of AEA hydrolysis could result in accumulation of endocannabinoids, which could alter normal endocannabinoid transmission during brain maturation.
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PMID:Effect of developmental chlorpyrifos exposure, on endocannabinoid metabolizing enzymes, in the brain of juvenile rats. 2150 91

The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) play vital roles during nervous system development. The degradation of 2-AG and AEA is mediated by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. These enzymes are inhibited following developmental chlorpyrifos (CPF) exposure. To investigate whether this inhibition is persistent or whether accumulation of endocannabinoids in the brain occurs, 10-day-old rat pups were orally exposed daily for 7 days to either corn oil or increasing dosages of CPF (1, 2.5, or 5mg/kg), and forebrains were collected at 4, 12, 24, and 48h following the last administration. All dosages inhibited cholinesterase (ChE), FAAH, and MAGL, and elevated AEA and 2-AG levels with the greatest effect occurring at 12h with ChE, FAAH, AEA, and 2-AG and at 4h with MAGL. With the high dosage, return to control levels occurred with 2-AG (48h) only. With the medium dosage, return to control levels occurred with MAGL, 2-AG, and AEA (48h) but not with ChE or FAAH. With the low dosage, return to control levels occurred with MAGL (12h), ChE and 2-AG (24h), and AEA (48h) but not with FAAH. With the lowest dosage, peak inhibition of FAAH (52%) is greater than that of ChE (24%) and that level of FAAH inhibition is sufficient to induce a persistent pattern of elevated AEA. It is possible that this pattern of elevation could alter the appropriate development of neuronal brain circuits.
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PMID:Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure. 2376

The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5mg/kg CPF by oral gavage. At 4 and 12h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4h, FAAH activity was significantly inhibited at 12h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of endocannabinoid signaling.
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PMID:Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition. 2437 5