Physiology and Immunology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
Chem Biol Interact. 2013 Mar 25;203(1):177-80. doi: 10.1016/j.cbi.2012.10.015. Epub 2012 Nov 2.
Human paraoxonase-1 (HuPON1) has been proposed as a catalytic bioscavenger of organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poisoning using two different paradigms. First, recombinant HuPON1 purified from cabbage loopers (iPON1; Trichoplusia ni) was administered to guinea pigs, followed by exposure to at least 2 times the median lethal dose (LD(50)) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic metabolite of the OP pesticide chlorpyrifos. In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then exposed to sequential doses of GD, VX, or (as reported previously) diazoxon, the toxic metabolite of the OP pesticide diazinon. In both animal models, the exogenously added HuPON1 protected animals against otherwise lethal doses of the OP pesticides but not against the nerve agents. Together, the results support prior modeling and in vitro activity data which suggest that wild-type HuPON1 does not have sufficient catalytic activity to provide in vivo protection against nerve agents.
人对氧磷酶-1（HuPON1）被提议作为有机磷（OP）农药和神经毒剂的催化生物清除剂。我们使用两种不同的模式评估了这种酶预防 OP 中毒的潜力。首先，从甘蓝夜蛾（iPON1；Trichoplusia ni）中纯化的重组 HuPON1 被施用于豚鼠，然后暴露于至少 2 倍的有机磷神经毒剂沙林（GB）、梭曼（GD）、塔崩（GA）和环沙林（GF）或 OP 农药毒死蜱的毒性代谢物氧乐果的半数致死剂量（LD50）以上。在第二个模型中，用诱导 HuPON1 表达的腺病毒感染小鼠，然后依次暴露于 GD、VX 或（如先前报道的）敌百虫的毒性代谢物二嗪农。在这两种动物模型中，外源性添加的 HuPON1 保护动物免受 OP 农药的致死剂量，但不能免受神经毒剂的侵害。总之，这些结果支持先前的建模和体外活性数据，表明野生型 HuPON1 没有足够的催化活性为机体提供对神经毒剂的体内保护。
