Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications.
Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications.
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DOI：
10.1006/taap.2001.9342
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发表时间：
2002-02
影响因子：
3.8
通讯作者：
G. B. Quistad;S. Sparks;Y. Segall;Daniel K. Nomura;J. Casida
中科院分区：
文献类型：
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作者：
G. B. Quistad;S. Sparks;Y. Segall;Daniel K. Nomura;J. Casida
脂肪酸酰胺水解酶（FAAH）通过调节内源性大麻素（例如，花生四烯酸酰胺）和水解睡眠诱导因子（油酰胺）。在这项研究中，几种有机磷农药和相关化合物显示出比神经病变靶向酯酶（NTE）更有效的小鼠脑FAAH的体内抑制剂，提出了FAAH抑制的潜在毒理学相关性的问题。这些FAAH选择性化合物包括三丁磷和（R）-辛基苯并二氧磷杂环氧化物，其在小鼠和母鸡中具有延迟的神经毒性作用，加上几种有机磷农药（例如，倍硫磷）被认为是人类的迟发性神经毒物。相对于NTE，寻找FAAH的高效和选择性抑制剂用作毒理学探针，最终发现辛基磺酰氟在体外2 nM和体内0.2 mg/kg时抑制FAAH 50%，而NTE在每种情况下的敏感性至少低100倍。更一般地说，研究揭示了12种FAAH的选择性体外抑制剂（主要是辛基磺酰基和辛基膦酰基衍生物）和9种NTE的选择性体外抑制剂（主要是苯并二氧磷杂环己烷氧化物和有机磷氟化物）。16种化合物的总体体内研究结果表明，预期AChE抑制与急性或胆碱能综合征相关，>70%的脑NTE抑制与延迟的神经毒性作用相关。令人惊讶的是，75-99%的脑FAAH抑制不会导致任何明显的神经毒性或行为变化（除了外源性大麻素作用的增强）。因此，小鼠脑中的FAAH抑制似乎不是有机磷农药诱导的神经毒性作用（胆碱能或中间综合征或迟发性神经毒性）的主要靶点。
Fatty acid amide hydrolase (FAAH) plays an important role in nerve function by regulating the action of endocannabinoids (e.g., anandamide) and hydrolyzing a sleep-inducing factor (oleamide). Several organophosphorus pesticides and related compounds are shown in this study to be more potent in vivo inhibitors of mouse brain FAAH than neuropathy target esterase (NTE), raising the question of the potential toxicological relevance of FAAH inhibition. These FAAH-selective compounds include tribufos and (R)-octylbenzodioxaphosphorin oxide with delayed neurotoxic effects in mice and hens plus several organophosphorus pesticides (e.g., fenthion) implicated as delayed neurotoxicants in humans. The search for a highly potent and selective inhibitor for FAAH relative to NTE for use as a toxicological probe culminated in the discovery that octylsulfonyl fluoride inhibits FAAH by 50% at 2 nM in vitro and 0.2 mg/kg in vivo and NTE is at least 100-fold less sensitive in each case. More generally, the studies revealed 12 selective in vitro inhibitors for FAAH (mostly octylsulfonyl and octylphosphonyl derivatives) and 9 for NTE (mostly benzodioxaphosphorin oxides and organophosphorus fluoridates). The overall in vivo findings with 16 compounds indicate the expected association of AChE inhibition with acute or cholinergic syndrome and >70% brain NTE inhibition with delayed neurotoxic action. Surprisingly, 75-99% brain FAAH inhibition does not lead to any overt neurotoxicity or change in behavior (other than potentiation of exogenous anandamide action). Thus, FAAH inhibition in mouse brain does not appear to be a primary target for organophosphorus pesticide-induced neurotoxic action (cholinergic or intermediate syndrome or delayed neurotoxicity).