Worek F, Diepold C, Eyer P
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Germany.
Arch Toxicol. 1999 Feb;73(1):7-14. doi: 10.1007/s002040050580.
Human poisoning by organophosphates bearing two methoxy groups, e.g. by malathion, paraoxon-methyl, dimethoate and oxydemeton-methyl, is generally considered to be rather resistant to oxime therapy. Since the oxime effectiveness is influenced not only by its reactivating potential but also by inhibition, aging and spontaneous reactivation kinetics, experiments were performed with human acetyl- (AChE) and butyrylcholinesterase (BChE) to determine the respective kinetic constants. The efficacy of obidoxime in reactivating dimethylphosphoryl-AChE was 40, 9 and 3 times higher than of HI 6, pralidoxime and HLö 7, respectively. Aging (t1/2 3.7 h) and spontaneous reactivation (t1/2 0.7 h) occurred concomitantly, with the portion of the aged enzyme being dependent on the presence of excess inhibitor. Calculation of steady-state AChE activity in the presence of inhibitor and oxime revealed that obidoxime was superior to pralidoxime. In addition, organophosphate concentrations up to 10(-6) M (paraoxon-methyl) and 10(-4) M (oxydemeton-methyl) could be counteracted at clinically relevant oxime concentrations (10 microM). These data indicate that oximes may effectively reactivate human dimethylphosphoryl-AChE. Failure of oximes may be attributed to megadose intoxications and to prolonged time intervals between poison uptake and oxime administration. The potency of the oximes to reactivate dimethylphosphoryl-BChE was much lower and the spontaneous reactivation slower (t1/2 9 h), while aging proceeded at a comparable rate. Thus, BChE activity determination for diagnosis and therapeutic monitoring may give no reliable information on AChE status.
人体因含有两个甲氧基的有机磷酸酯中毒，如因马拉硫磷、甲基对氧磷、乐果和氧化乐果中毒，一般认为对肟类疗法有较强抗性。由于肟的有效性不仅受其重活化潜力影响，还受抑制、老化和自发重活化动力学影响，因此开展了针对人体乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的实验，以确定各自的动力学常数。氯解磷定重活化二甲基磷酰化 - AChE的效力分别比HI 6、解磷定和HLö 7高40倍、9倍和3倍。老化（半衰期3.7小时）和自发重活化（半衰期0.7小时）同时发生，老化酶的比例取决于过量抑制剂的存在。在有抑制剂和肟存在的情况下计算稳态AChE活性，结果显示氯解磷定优于解磷定。此外，在临床相关的肟浓度（10微摩尔）下，高达10⁻⁶ M（甲基对氧磷）和10⁻⁴ M（氧化乐果）的有机磷酸酯浓度可被抵消。这些数据表明肟类可有效重活化人体二甲基磷酰化 - AChE。肟类治疗失败可能归因于超大剂量中毒以及中毒摄入与肟给药之间的时间间隔延长。肟类重活化二甲基磷酰化 - BChE的效力要低得多，自发重活化也较慢（半衰期9小时），而老化速率相当。因此，测定BChE活性用于诊断和治疗监测可能无法提供有关AChE状态的可靠信息。
