Wetherell J R, French M C
Biology Division, Chemical Defence Establishment, Salisbury, Wiltshire, U.K.
Biochem Pharmacol. 1991 Jul 15;42(3):515-20. doi: 10.1016/0006-2952(91)90313-t.
Plasma and red cells from a variety of animal species were used to demonstrate that there is a relationship between the decarbamoylation rates of physostigmine-inhibited plasma and red cell cholinesterases in vitro and the effectiveness of carbamate pretreatment against nerve agent poisoning reported in the literature. Decarbamoylation rates were faster in the non-human primates than in the guinea-pig, and carbamate pretreatment is more effective in these species than in the guinea-pig. The data for the decarbamoylation rates of physostigmine-inhibited enzymes suggests that the non-human primates are the best animal model for extrapolation of protection studies from animal species to man. Control values for red cell acetylcholinesterase (AChE) activity (mumol/min/mL blood) using acetylthiocholine (1 mM) were higher in the human (4.98) and the rhesus monkey (4.14) than in the marmoset (0.84) and the guinea-pig (0.83). Plasma cholinesterase (ChE) activity (mumol/min/mL plasma) using butyrylthiocholine (10 mM) was highest in the rhesus monkey (9.29), intermediate in human (5.10) and guinea-pig (6.06), and lowest in the marmoset (4.07). There was a species difference in the relative activity of AChE: ChE in blood, human (65:35), rhesus monkey (45:55), marmoset (30:70) and guinea-pig (20:80). The rate of recovery of red cell AChE and plasma ChE activities, following incubation of whole blood with physostigmine (1 x 10(-7) M), was in the order human greater than rhesus monkey greater than marmoset greater than guinea-pig. During the incubation of red cells with physostigmine there was little recovery of AChE activity for 3-4 hr in any species. During the incubation of plasma with physostigmine there was complete recovery of ChE activity by 2-3 hr in the human and rhesus monkey and a significant recovery by 3 hr in the marmoset and guinea-pig. This suggests that a component of plasma, possibly ChE, was responsible for the degradation of physostigmine, presumably by hydrolysis. There was a marked species difference in the decarbamoylation rates of physostigmine-inhibited enzyme. In the red cell the t1/2 values (min) were 14.8 (human), 21.2 (rhesus monkey), 17.9 (marmoset) and 31.9 (guinea-pig). In the plasma the t1/2 values (min) were 11.2 (human), 32.9 (rhesus monkey), 44.1 (marmoset) and 52.4 (guinea-pig).
使用来自多种动物物种的血浆和红细胞来证明，体外毒扁豆碱抑制的血浆和红细胞胆碱酯酶的脱氨甲酰化速率与文献中报道的氨基甲酸酯预处理对神经毒剂中毒的有效性之间存在关联。非人灵长类动物的脱氨甲酰化速率比豚鼠快，并且氨基甲酸酯预处理在这些物种中比在豚鼠中更有效。毒扁豆碱抑制酶的脱氨甲酰化速率数据表明，非人灵长类动物是将保护研究从动物物种外推至人类的最佳动物模型。使用乙酰硫代胆碱（1 mM）时，人（4.98）和恒河猴（4.14）的红细胞乙酰胆碱酯酶（AChE）活性（μmol/分钟/毫升血液）的对照值高于狨猴（0.84）和豚鼠（0.83）。使用丁酰硫代胆碱（10 mM）时，血浆胆碱酯酶（ChE）活性（μmol/分钟/毫升血浆）在恒河猴中最高（9.29），在人（5.10）和豚鼠（6.06）中居中，在狨猴中最低（4.07）。血液中AChE与ChE的相对活性存在物种差异：人（65:35）、恒河猴（45:55）、狨猴（30:70）和豚鼠（20:80）。用毒扁豆碱（1×10⁻⁷ M）孵育全血后，红细胞AChE和血浆ChE活性的恢复速率顺序为：人＞恒河猴＞狨猴＞豚鼠。在任何物种中，红细胞与毒扁豆碱孵育期间，3 - 4小时内AChE活性几乎没有恢复。在血浆与毒扁豆碱孵育期间，人及恒河猴在2 - 3小时时ChE活性完全恢复，狨猴和豚鼠在3小时时有显著恢复。这表明血浆中的一种成分，可能是ChE，负责毒扁豆碱的降解，推测是通过水解。毒扁豆碱抑制酶的脱氨甲酰化速率存在明显的物种差异。在红细胞中，t1/2值（分钟）分别为14.8（人）、21.2（恒河猴）、17.9（狨猴）和31.9（豚鼠）。在血浆中，t1/2值（分钟）分别为11.2（人）、32.9（恒河猴）（此处原文可能有误，按照逻辑推测应为其他值，暂按原文翻译）、44.1（狨猴）和52.4（豚鼠）。
