Investigation of the toxic mechanism of oximes which are used in the treatment of poisoning by nerve agents

甲基碘化吡啶醛肟（PAM）型肟4-PAO，它可以重新激活被烷基膦酸盐抑制的AChE并穿透血脑屏障，预计可有效地重新激活脑中被阻断的胆碱酯酶。然而，4-PAO的毒性尚未被详细研究。本研究采用心电图分析方法，观察了4-PAO对大鼠心脏收缩活动的影响。4-PAO对房室传导系统的抑制作用强于2-PAM。此外，不仅4-PAO，2-PAM也抑制肌球蛋白的固有K+-EDTA-ATP酶催化活性，表明肟可能直接与肌球蛋白分子的催化中心相互作用。对于小于4 μ M的4-PAO、2-PAM、4-PAPE、双肟和DAM（其对应于2-PAM的临床剂量）没有观察到显著抑制。4-PAO的毒性机制有待进一步研究。

The pyridinium aldoxime methiodide (PAM)-type oxime 4-PAO, which can reactivate AChE inhibited by alkylphosphonate and penetrate the blood-brain barrier, is expected to be effective for reactivating blocked cholinesterase in the brain. However, the toxicity of 4-PAO has not yet been investigated in detail. The present study investigated the effects of 4-PAO on the contractile activity of the rat heart using electrocardiography analysis. 4-PAO was suggested to inhibit the atrioventricular conduction system more strongly than 2-PAM. In addition, not only 4-PAO but also 2-PAM inhibited the inherent K+-EDTA-ATPase catalytic activity of myosin, indicating that oximes might interact directly with the catalytic center of the myosin molecule. No significant inhibition was observed for less than 4uM 4-PAO, 2-PAM, 4-PAPE, obidoxime and DAM, which correspond to the clinical dose of 2-PAM. Further studies are required to clarify the mechanism of 4-PAO toxicity.