Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides

Organophosphorus (OP) compound-induced inhibition of acetyl-cholinesterase (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 targe t for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxo n inhibits 50% of the FAAH activity (IC50 at 15 min, 25 degreesC, pH 9.0) i n vitro at 40-56 nM for mouse brain and liver, whereas methyl arachidonyl p hosphonofluoridate, ethyl octylphosphonofluoridate (EOPE), oleyl-4H-1,3,2-b enzodioxaphosphorin 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 grea ter than or equal to 200-fold higher potency than for AChE. Five OP pestici des 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 me thamidophos occurs near acutely toxic levels, profenofos and tribufos are e ffective 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 < greater than or equal to>76% in brain depresses movement of mice administer ed anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pe sticides 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 read to reduced limb mobili ty as a secondary neurotoxic effect, (C) 2001 academic Press.