Research School of Chemistry, Australian National University, Australian Capital Territory 0200, Australia.
New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772, USA.
Toxicology. 2014 Mar 20;317:1-5. doi: 10.1016/j.tox.2014.01.003. Epub 2014 Jan 18.
Organophosphorus (OP) pesticides are a diverse class of acetylcholinesterase (AChE) inhibitors that are responsible for tremendous morbidity and mortality worldwide, killing approximately 300,000 people annually. Enzymatic hydrolysis of OPs is a potential therapy for acute poisoning. OpdA, an OP hydrolase isolated from Agrobacterium radiobacter, has been shown to decrease lethality in rodent models of OP poisoning. This study investigated the effects of OpdA on AChE activity, plasma concentrations of OP, and signs of toxicity after administration of dichlorvos to nonhuman primates. A dose of 75 mg/kg dichlorvos given orally caused apnea within 10 min with a progressive decrease in heart rate. Blood AChE activity decreased to zero within 10 min. Respirations and AChE activity did not recover. The mean dichlorvos concentration rose to a peak of 0.66 μg/ml. Treated monkeys received 1.2mg/kg OpdA iv immediately after poisoning with dichlorvos. In Opda-treated animals, heart and respiratory rates were unchanged from baseline over a 240-minute observation period. AChE activity slowly declined, but remained above 25% of baseline for the entire duration. Dichlorvos concentrations reached a mean peak of 0.19 μg/ml at 40 min after poisoning and decreased to a mean of 0.05 μg/ml at 240 min. These results show that OpdA hydrolyzes dichlorvos in an African green monkey model of lethal poisoning, delays AChE inhibition, and prevents lethality.
有机磷 (OP) 农药是一类广泛的乙酰胆碱酯酶 (AChE) 抑制剂，在全球范围内导致了巨大的发病率和死亡率，每年约有 30 万人因此死亡。OP 的酶水解是急性中毒的一种潜在治疗方法。从根癌农杆菌中分离出的 OP 水解酶 OpdA 已被证明可降低 OP 中毒啮齿动物模型的致死率。本研究探讨了 OpdA 对 AChE 活性、OP 血浆浓度和给予二氯氧磷后非人类灵长类动物毒性体征的影响。口服给予 75mg/kg 的二氯氧磷在 10 分钟内引起呼吸暂停，并伴有心率逐渐下降。血液 AChE 活性在 10 分钟内降至零。呼吸和 AChE 活性未恢复。二氯氧磷的平均浓度上升至 0.66μg/ml 的峰值。中毒后立即给予 1.2mg/kg 的 OpdA 静脉注射治疗猴子。在 Opda 处理的动物中，心和呼吸率在 240 分钟的观察期间与基线相比没有变化。AChE 活性缓慢下降，但在整个过程中仍保持在基线的 25%以上。二氯氧磷浓度在中毒后 40 分钟达到 0.19μg/ml 的平均峰值，并在 240 分钟降至 0.05μg/ml 的平均水平。这些结果表明，OpdA 在致命性中毒的非洲绿猴模型中水解二氯氧磷，延迟 AChE 抑制，并防止致死。
