Each lipase has a unique sensitivity profile for organophosphorus inhibitors
Each lipase has a unique sensitivity profile for organophosphorus inhibitors
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DOI：
10.1093/toxsci/kfj124
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发表时间：
2006-05-01
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;Liang, SN;Casida, JE
对有机磷 (OP) 抑制剂敏感的脂肪酶在细胞调节、营养和疾病中发挥着关键作用，但人们对哺乳动物的毒理学方面知之甚少。为了帮助填补这一空白，我们在标准条件（25 摄氏度，孵育 15 分钟）下对六种脂肪酶或脂肪酶样蛋白的 OP 敏感性进行了体外分析。肝素后血清脂肪酶、脂蛋白脂肪酶 (LPL)（两种来源）、胰脂肪酶、单酰甘油 (MAG) 脂肪酶、胆固醇酯酶和 KIAA1363 与 32 种 OP 农药和相关化合物一起考虑。大鼠血清中的肝素后脂肪分解活性可被 14 种 OP 抑制，包括毒死蜱 oxon (IC50 50-97 nM)。 LPL（牛奶和假单胞菌）通常不太受杀虫剂或活化的oxon的抑制，但乳酶对六种氟膦酸盐和苯并二氧磷氧化物非常敏感（IC50 7-20 nM）。猪胰腺脂肪酶对二辛基 4-硝基苯基磷酸酯 (IC50 8 nM)、小鼠大脑的 MAG 脂肪酶对 O-4-硝基苯基甲基十二烷基次膦酸酯 (IC50 0.6 nM) 和胆固醇酯酶（牛胰腺）对所有测试的 OP 类别非常敏感（17 种化合物的 IC50 < 10 nM）。 KIAA1363 对多种 OP 敏感，包括两种 O-4-硝基苯基化合物 (IC50 3-4 nM)。总而言之，八种有机磷农药（毒死蜱、重氮磷、对氧磷、敌敌畏和四种非农药）对 28 种丝氨酸水解酶（包括脂肪酶）的抑制表明，脑乙酰胆碱酯酶通常不如丁酰胆碱酯酶、肝酯酶、胆固醇酯酶和 KIAA1363 敏感。一般来说，每种脂肪酶（如每种丝氨酸水解酶）具有不同的 OP 敏感性谱，并且各个 OP 具有独特的丝氨酸水解酶抑制效力排名。
Lipases sensitive to organophosphorus (OP) inhibitors play critical roles in cell regulation, nutrition, and disease, but little is known on the toxicological aspects in mammals. To help fill this gap, six lipases or lipase-like proteins are assayed for OP sensitivity in vitro under standard conditions (25 degrees C, 15 min incubation). Postheparin serum lipase, lipoprotein lipase (LPL) (two sources), pancreatic lipase, monoacylglycerol (MAG) lipase, cholesterol esterase, and KIAA1363 are considered with 32 OP pesticides and related compounds. Postheparin lipolytic activity in rat serum is inhibited by 14 OPs, including chlorpyrifos oxon (IC50 50-97 nM). LPL (bovine milk and Pseudomonas) generally is less inhibited by the insecticides or activated oxons, but the milk enzyme is very sensitive to six fluorophosphonates and benzodioxaphosphorin oxides (IC50 7-20 nM). Porcine pancreatic lipase is very sensitive to dioctyl 4-nitrophenyl phosphate (IC50 8 nM), MAG lipase of mouse brain to O-4-nitrophenyl methyldodecylphosphinate (IC50 0.6 nM), and cholesterol esterase (bovine pancreas) to all of the classes of OPs tested (IC50 < 10 nM for 17 compounds). KIAA1363 is sensitive to numerous OPs, including two O-4-nitrophenyl compounds (IC50 3-4 nM). In an overview, inhibition of 28 serine hydrolases (including lipases) by eight OPs (chlorpyrifos oxon, diazoxon, paraoxon, dichlorvos, and four nonpesticides) showed that brain acetylcholinesterase is usually less sensitive than butyrylcholinesterase, liver esterase, cholesterol esterase, and KIAA1363. In general, each lipase (like each serine hydrolase) has a different spectrum of OP sensitivity, and individual OPs have unique ranking of potency for inhibition of serine hydrolases.