Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides.
Organophosphorus (OP) compound-induced inhibition of acetylcholinesterase (AChE) and neuropathy target esterase explains the rapid onset and delayed neurotoxic effects, respectively, for OP insecticides and related compounds but apparently not a third or intermediate syndrome with delayed onset and reduced limb mobility. This investigation tests the hypothesis that fatty acid amide hydrolase (FAAH), a modulator of endogenous signaling compounds affecting sleep (oleamide) and analgesia (anandamide), is a sensitive target for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxon inhibits 50% of the FAAH activity (IC50 at 15 min, 25 degrees C, pH 9.0) in vitro at 40--56 nM for mouse brain and liver, whereas methyl arachidonyl phosphonofluoridate, ethyl octylphosphonofluoridate (EOPF), oleyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (oleyl-BDPO), and dodecyl-BDPO give IC50s of 0.08--1.1 nM. These BDPOs and EOPF inhibit mouse brain FAAH in vitro with > or =200-fold higher potency than for AChE. Five OP pesticides inhibit 50% of the brain FAAH activity (ED50) at <30 mg/kg 4 h after ip administration to mice; while inhibition by chlorpyrifos, diazinon, and methamidophos occurs near acutely toxic levels, profenofos and tribufos are effective at asymptomatic doses. Two BDPOs (dodecyl and phenyl) and EOPF are potent inhibitors of FAAH in vivo (ED50 0.5--6 mg/kg). FAAH inhibition of > or =76% in brain depresses movement of mice administered anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pesticides and related inhibitors of FAAH potentiate the cannabinoid activity of anandamide in mice. More generally, OP compound-induced FAAH inhibition and the associated anandamide accumulation may lead to reduced limb mobility as a secondary neurotoxic effect.
Quistad
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GB
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 114 Wellman Hall, Berkeley, California, 94720-3112, USA.
Sparks
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SE
Casida
J E
JE
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D002186:Cannabinoids / Q000494:pharmacology; D004390:Chlorpyrifos / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003976:Diazinon / Q000494:pharmacology; D004357:Drug Synergism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D009420:Nervous System / Q000187:drug effects*; D063086:Organothiophosphates / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D002186:Cannabinoids; D004390:Chlorpyrifos; D002800:Cholinesterase Inhibitors; D003976:Diazinon; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007306:Insecticides; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C024273:profenofos; C014655:methamidophos; C078814:anandamide