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Link to original content: https://pubmed.ncbi.nlm.nih.gov/18495101
Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids - PubMed Skip to main page content
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Review
. 2008 Sep 25;175(1-3):355-64.
doi: 10.1016/j.cbi.2008.04.008. Epub 2008 May 20.

Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids

John E Casida  1 , Daniel K Nomura, Sarah C Vose, Kazutoshi Fujioka
Affiliations
Review

Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids

John E Casida et al. Chem Biol Interact. .

Abstract

Lipases play key roles in nearly all cells and organisms. Potent and selective inhibitors help to elucidate their physiological functions and associated metabolic pathways. Organophosphorus (OP) compounds are best known for their anticholinesterase properties but selectivity for lipases and other targets can also be achieved through structural optimization. This review considers several lipid systems in brain modulated by highly OP-sensitive lipases. Neuropathy target esterase (NTE) hydrolyzes lysophosphatidylcholine (lysoPC) as a preferred substrate. Gene deletion of NTE in mice is embryo lethal and the heterozygotes are hyperactive. NTE is very sensitive in vitro and in vivo to direct-acting OP delayed neurotoxicants and the related NTE-related esterase (NTE-R) is also inhibited in vivo. KIAA1363 hydrolyzes acetyl monoalkylglycerol ether (AcMAGE) of the platelet-activating factor (PAF) de novo biosynthetic pathway and is a marker of cancer cell invasiveness. It is also a detoxifying enzyme that hydrolyzes chlorpyrifos oxon (CPO) and some other potent insecticide metabolites. Monoacylglycerol lipase and fatty acid amide hydrolase regulate endocannabinoid levels with roles in motility, pain and memory. Inhibition of these enzymes in mice by OPs, such as isopropyl dodecylfluorophosphonate (IDFP), leads to dramatic elevation of brain endocannabinoids and distinct cannabinoid-dependent behavior. Hormone-sensitive lipase that hydrolyzes cholesteryl esters and diacylglycerols is a newly recognized in vivo CPO- and IDFP-target in brain. The OP chemotype can therefore be used in proteomic and metabolomic studies to further elucidate the biological function and toxicological significance of lipases in lipid metabolism. Only the first steps have been taken to achieve appropriate selective action for OP therapeutic agents.

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Figures

Fig. 1
Fig. 1
Structures of OP insecticides and analogs. CPO, POX and DOX are metabolites of the important insecticides chlorpyrifos (CPF), parathion (PT) and diazinon, respectively. Profenofos and dichlorvos are insecticides while most of the others are compounds designed to achieve potency or selectivity. TOCP, mipafox, EOPF and IDFP are delayed neurotoxicants.
Fig. 2
Fig. 2
OP sensitivity of mouse brain serine hydrolases determined by ABPP analysis. A. In vitro inhibition assessed by in-gel ABPP using FP-rhodamine. B. In vivo inhibition 4 h after ip treatment with IDFP (10 mg/kg) and CPO (4 mg/kg) compared with control determined by ABPP-MudPIT using FP-biotin. Spectral counts refer to the total amount of uninhibited enzyme.
Fig. 3
Fig. 3
Selected OP-sensitive lipase targets and their functions.
Fig. 4
Fig. 4
NTE regulates phospholipid metabolism as a lysoPC hydrolase.
Fig. 5
Fig. 5
Correlation of inhibitor sensitivity and specificity profiles of LysoPC hydrolase activities of rNTE with those of human brain, erythrocytes and lymphocytes. The inhibitors in each case are nine OPs and one carbamate.
Fig. 6
Fig. 6
KIAA1363 modulates ether lipid metabolism and OP detoxification.
Fig. 7
Fig. 7
KIAA1363 tissue distribution and role in ether lipid metabolism and OP detoxification determined with +/+ and −/− mice. A. Tissue distribution for AcMAGE and CPO hydrolysis and FP-rhodamine labeling of membrane proteins B. Involvement in PAF biosynthetic pathway shown by products from in vitro incubation of mouse brain membranes with 0 or 100 µM CPO (preincubation), 10 µM AcMAGE and 100 µM CDP-choline. C. CPF and PT are less toxic to +/+ than −/− mice
Fig. 8
Fig. 8
MAGL and FAAH regulate endocannabinoid levels.
Fig. 9
Fig. 9
IDFP-induced activation of the endocannabinoid system 4 h posttreatment. A. Elevation of 2-AG and AEA levels with corresponding lowering of AA. B. CB1 antagonist (AM251) blocks IDFP-induced changes in behavior. C. CB1 knockout mice are protected from IDFP cannabinoid effects.
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References

    1. Quistad GB, Barlow C, Winrow CJ, Sparks SE, Casida JE. Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proc. Natl. Acad. Sci. U.S.A. 2003;100:7983–7987. - PMC - PubMed
    1. Chiang KP, Niessen S, Saghatelian A, Cravatt BF. An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling. Chem. Biol. 2006;13:1041–1050. - PubMed
    1. Shi Y, Burn P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat. Rev. Drug Discov. 2004;3:695–710. - PubMed
    1. Macphee CH, Nelson J, Zalewski A. Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target. Curr. Opin. Pharmacol. 2006;7:154–161. - PubMed
    1. Casida JE, Quistad GB. Serine hydrolase targets of organophosphorus toxicants. Chem. Biol. Interact. 2005;157–158:277–283. - PubMed

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