Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice
Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice
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DOI：
10.1016/j.taap.2005.10.007
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发表时间：
2006-02-15
影响因子：
3.8
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Quistad, GB;Klintenberg, R;Casida, JE
大麻素系统的三种组分对所选的有机磷（OP）化合物敏感：单酰基甘油（MAG）脂肪酶，其水解主要的内源性激动剂2-花生四烯酰甘油（2-AG）;脂肪酸酰胺水解酶（FAAH），其切割以较少量存在的激动剂花生四烯酸; CB 1受体本身。本研究考虑大麻素系统的哪种成分最可能导致OP诱导的小鼠运动功能减退。我们的实验室和其他人的结构活性研究的规则，对主要参与的直接有毒物质CB 1受体相互作用的选择OP。因此，注意力集中在MAG脂肪酶和FAAH的OP敏感性，测定19种结构不同的OP化学品（农药，其代谢物和设计师化合物）在体外抑制这两种酶。使用三个O-烷基，观察到显著的高效力和低选择性。（C-1，C-2，C-3）烷基膦酰氟化物（C-8、C-12）（IC 50 0.60-3.0 nM），5个S-烷基（C-5、C-7、C-9）和烷基（C-10，C-12）苯并二氧磷杂环氧化物（IC 50 0.15-5.7 nM）和一种OP杀虫剂代谢物（毒死蜱，IC 50 34-40 nM）。在ip处理的小鼠中，1-30 mg/kg的OP比MAG脂肪酶更有效地抑制脑FAAH，但FAAH抑制与运动功能减退无关。然而，经烷基氟膦酸酯处理的小鼠显示出运动功能减退、MAG脂肪酶活性抑制和2-AG升高的严重程度的剂量依赖性增加。中度至重度运动功能减退伴有64 - 86% MAG脂肪酶抑制和脑2-AG水平约6倍升高。因此，OP诱导的MAG脂肪酶抑制似乎导致2-AG升高和相关的运动功能减退。(c)2005年爱思唯尔公司All rights reserved.
Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure-activity studies by our laboratory and others rule against major involvement of a direct toxicant-CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicals (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C-1, C-2, C-3) alkylphosphonofluoridates (C-8, C-12) (IC50 0.60-3.0 nM), five S-alkyl (C-5, C-7, C-9) and alkyl (C-10, C-12) benzodioxaphosphorin oxides (IC50 0.15-5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34-40 nM). In ip-treated mice, the OPs at 1-30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility. (c) 2005 Elsevier Inc. All rights reserved.