Quistad Gary B, Liang Shannon N, Fisher Karl J, Nomura Daniel K, Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Toxicol Sci. 2006 May;91(1):166-72. doi: 10.1093/toxsci/kfj124. Epub 2006 Jan 31.
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.
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，但在哺乳动物的毒理学方面却知之甚少。为了填补这一空白，在标准条件（25摄氏度，孵育15分钟）下对六种脂肪酶或类脂肪酶蛋白进行了体外OP敏感性测定。研究考虑了肝素后血清脂肪酶、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，以及32种OP农药和相关化合物。大鼠血清中的肝素后脂解活性受到14种OP的抑制，包括毒死蜱氧磷（IC50为50 - 97 nM）。LPL（牛乳和假单胞菌来源）通常受杀虫剂或活化的氧磷抑制程度较小，但牛乳中的该酶对六种氟膦酸盐和苯并二氧磷杂环己烷氧化物非常敏感（IC50为7 - 20 nM）。猪胰脂肪酶对磷酸二辛酯4 - 硝基苯酯非常敏感（IC50为8 nM），小鼠脑MAG脂肪酶对O - 4 - 硝基苯基甲基十二烷基次膦酸酯敏感（IC50为0.6 nM），牛胰腺胆固醇酯酶对所有测试的OP类别都敏感（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为3 - 4 nM）。总体而言，八种OP（毒死蜱氧磷、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）抑制作用的研究表明，脑乙酰胆碱酯酶通常比对丁酰胆碱酯酶、肝酯酶、胆固醇酯酶和KIAA1363的敏感性低。一般来说，每种脂肪酶（如同每种丝氨酸水解酶）对OP的敏感性谱不同，且每种OP对丝氨酸水解酶抑制效力的排名也具有独特性。
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