Nomura_2008_Toxicol.Appl.Pharmacol_228_42

Reference

Title : Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification - Nomura_2008_Toxicol.Appl.Pharmacol_228_42
Author(s) : Nomura DK , Fujioka K , Issa RS , Ward AM , Cravatt BF , Casida JE
Ref : Toxicol Appl Pharmacol , 228 :42 , 2008
Abstract :

Serine hydrolase KIAA1363 is an acetyl monoalkylglycerol ether (AcMAGE) hydrolase involved in tumor cell invasiveness. It is also an organophosphate (OP) insecticide-detoxifying enzyme. The key to understanding these dual properties was the use of KIAA1363 +/+ (wildtype) and -/- (gene deficient) mice to define the role of this enzyme in brain and other tissues and its effectiveness in vivo in reducing OP toxicity. KIAA1363 was the primary AcMAGE hydrolase in brain, lung, heart and kidney and was highly sensitive to inactivation by chlorpyrifos oxon (CPO) (IC50 2 nM) [the bioactivated metabolite of the major insecticide chlorpyrifos (CPF)]. Although there was no difference in hydrolysis product monoalkylglycerol ether (MAGE) levels in +/+ and -/- mouse brains in vivo, isopropyl dodecylfluorophosphonate (30 mg/kg) and CPF (100 mg/kg) resulted in 23-51% decrease in brain MAGE levels consistent with inhibition of AcMAGE hydrolase activity. On incubating +/+ and -/- brain membranes with AcMAGE and cytidine-5'-diphosphocholine, the absence of KIAA1363 activity dramatically increased de novo formation of platelet-activating factor (PAF) and lyso-PAF, signifying that metabolically-stabilized AcMAGE can be converted to this bioactive lipid in brain. On considering detoxification, KIAA1363 -/- mice were significantly more sensitive than +/+ mice to ip-administered CPF (100 mg/kg) and parathion (10 mg/kg) with increased tremoring and mortality that correlated for CPF with greater brain acetylcholinesterase inhibition. Docking AcMAGE and CPO in a KIAA1363 active site model showed similar positioning of their acetyl and trichloropyridinyl moieties, respectively. This study establishes the relevance of KIAA1363 in ether lipid metabolism and OP detoxification.

PubMedSearch : Nomura_2008_Toxicol.Appl.Pharmacol_228_42
PubMedID: 18164358
Gene_locus related to this paper: human-NCEH1

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Citations formats

Nomura DK, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE (2008)
Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification
Toxicol Appl Pharmacol 228 :42

Nomura DK, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE (2008)
Toxicol Appl Pharmacol 228 :42