Allon N, Raveh L, Gilat E, Cohen E, Grunwald J, Ashani Y
Israel Institute for Biological Research, Ness-Ziona, Israel.
Toxicol Sci. 1998 Jun;43(2):121-8. doi: 10.1006/toxs.1998.2463.
Human butyrylcholinesterase (HuBChE) has previously been shown to protect mice, rats, and monkeys against multiple lethal toxic doses of organophosphorus (OP) anticholinesterases that were challenged by i.v. bolus injections. This study examines the concept of using a cholinesterase scavenger as a prophylactic measure against inhalation toxicity, which is the more realistic simulation of exposure to volatile OPs. HuBChE-treated awake guinea pigs were exposed to controlled concentration of soman vapors ranging from 417 to 430 micrograms/liter, for 45 to 70 s. The correlation between the inhibition of circulating HuBChE and the dose of soman administered by sequential i.v. injections and by respiratory exposure indicated that the fraction of the inhaled dose of soman that reached the blood was 0.29. HuBChE to soman molar ratio of 0.11 was sufficient to prevent the manifestation of toxic signs in guinea pigs following exposure to 2.17x the inhaled LD50 dose of soman (ILD50, 101 micrograms/kg). A slight increase in HuBChE:soman ratio (0.15) produced sign-free animals after two sequential respiratory exposures with a cumulative dose of 4.5x ILD50. Protection was exceptionally high and far superior to the currently used traditional approach that consisted of pretreatment with pyridostigmine and postexposure combined administration of atropine, benactyzine, and an oxime reactivator. Quantitative analysis of the results suggests that in vivo sequestration of soman, and presumably other OPs, by exogenously administered HuBChE, is independent of the species used or the route of challenge entry. This assuring conclusion significantly expands the database of the bioscavenger strategy that now offers a dependable extrapolation from animals to human.
此前已证明，人丁酰胆碱酯酶（HuBChE）可保护小鼠、大鼠和猴子免受多次静脉推注给予的致死剂量有机磷（OP）抗胆碱酯酶的侵害。本研究探讨了使用胆碱酯酶清除剂作为预防吸入毒性的措施这一概念，吸入毒性是对挥发性OP暴露更现实的模拟。经HuBChE处理的清醒豚鼠暴露于浓度为417至430微克/升的梭曼蒸气中45至70秒。通过静脉序贯注射和呼吸道暴露给予梭曼的剂量与循环HuBChE抑制之间的相关性表明，吸入的梭曼剂量中到达血液的部分为0.29。HuBChE与梭曼的摩尔比为0.11足以防止豚鼠在暴露于2.17倍吸入半数致死剂量梭曼（吸入半数致死剂量，101微克/千克）后出现中毒症状。HuBChE与梭曼的比例略有增加（0.15），在两次连续呼吸道暴露且累积剂量为4.5倍吸入半数致死剂量后，产生了无中毒症状的动物。保护效果非常高，远远优于目前使用的传统方法，传统方法包括用吡啶斯的明预处理以及暴露后联合给予阿托品、苯那辛和肟类复活剂。对结果的定量分析表明，外源性给予的HuBChE在体内对梭曼以及可能对其他OP的隔离作用，与所使用的物种或攻击进入途径无关。这一可靠的结论显著扩展了生物清除剂策略的数据库，现在该策略可从动物可靠地外推至人类。
