Maxwell Donald M, Brecht Karen M, Koplovitz Irwin, Sweeney Richard E
US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
Arch Toxicol. 2006 Nov;80(11):756-60. doi: 10.1007/s00204-006-0120-2. Epub 2006 Jun 13.
The hypothesis that acetylcholinesterase (AChE) inhibition is the mechanism of toxicity of organophosphorus (OP) compounds was examined by mathematically modeling the in vivo lethal effects of OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition. Mortality dose-response curves for several OP compounds (i.e., VX, soman, cyclosarin, sarin, tabun, diisopropylfluorophosphate and paraoxon) exhibited steep probit slopes (> 9.6) in guinea pigs. Steep probit slopes were also observed when the mortality dose-response curves for soman were examined in mice, rats, rabbits and non-human primates. The consistently steep probit slopes of the dose-response curves for highly toxic OP compounds suggested that these compounds have a single specific mechanism of toxicity regardless of the OP compound or the species in which it was tested. Regression analysis indicated that 93% of the 3,280-fold variation in the median lethal doses (i.e., LD(50)) of OP compounds in rats was explained by the variation in their in vitro rate constants for inhibition of AChE. Conversely, 91% of the 23-fold variation in the ability of the oximes pralidoxime and obidoxime to protect against the toxicity of OP compounds in guinea pigs was explained by the variation in the in vitro ability of oximes to reactivate OP-inhibited AChE. The best explanation for this variety of observations was that the primary mechanism of in vivo toxicity for highly toxic OP compounds is the inhibition of AChE, and the residual unexplained variation in OP toxicity that might be explained by other mechanisms represents < 10% of the total variation in OP toxicity.
通过对有机磷（OP）化合物的体内致死效应进行数学建模，并确定由乙酰胆碱酯酶（AChE）抑制所解释的OP毒性变化量，来检验AChE抑制是OP化合物毒性机制这一假说。几种OP化合物（即VX、梭曼、环沙林、沙林、塔崩、二异丙基氟磷酸酯和对氧磷）在豚鼠中的死亡率剂量反应曲线呈现出陡峭的概率单位斜率（>9.6）。在小鼠、大鼠、兔子和非人类灵长类动物中检测梭曼的死亡率剂量反应曲线时，也观察到了陡峭的概率单位斜率。高毒性OP化合物剂量反应曲线始终呈现陡峭的概率单位斜率，这表明这些化合物具有单一的特定毒性机制，与所测试的OP化合物或物种无关。回归分析表明，大鼠中OP化合物半数致死剂量（即LD(50)）3280倍的变化中有93%可由其体外抑制AChE的速率常数变化来解释。相反，在豚鼠中，肟类化合物解磷定和双复磷预防OP化合物毒性能力23倍的变化中有91%可由肟类化合物体外重新激活被OP抑制的AChE的能力变化来解释。对这些各种观察结果的最佳解释是，高毒性OP化合物体内毒性的主要机制是AChE抑制，而OP毒性中可能由其他机制解释的剩余未解释变化占OP毒性总变化的比例不到10%。
