Maxwell D M
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425.
Toxicol Appl Pharmacol. 1992 Jun;114(2):306-12. doi: 10.1016/0041-008x(92)90082-4.
The ability of endogenous carboxylesterase (CaE) to protect against the lethal effects of a variety of organophosphorus (OP) compounds was examined in rats. The in vivo protection provided by endogenous CaE was measured by the difference in the LD50 values of OP compounds in control rats and rats whose CaE activity had been inhibited by sc injection with 2 mg/kg of 2-(O-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide. Endogenous CaE provided significant protection against the in vivo toxicity of soman, sarin, tabun, and paraoxon, but not against dichlorvos, diisopropyl fluorophosphate, or ethoxymethyl-S-[2-(diisopropylamino)ethyl] thiophosphonate (VX). The relationship between the in vivo CaE protection against OP compounds and their relative reactivities with CaE and acetylcholinesterase (AChE) was evaluated by measuring the in vitro bimolecular rate constants (ki) for inhibition of plasma CaE and brain AChE. Except for VX, ki values for CaE inhibition varied less than 10-fold while ki values for AChE inhibition varied 10(5)-fold. The degree of in vivo inhibition of CaE by equitoxic doses of the OP compounds increased as the CaE/AChE ki ratio increased. However, the protective ratio of the LD50 values in control vs CaE-inhibited rats decreased as the CaE/AChE ki ratio increased. This inverse relationship between in vivo CaE protection and relative in vitro reactivity for CaE suggested that CaE detoxication is more important for highly toxic OP compounds (i.e., compounds with high AChE ki values and low LD50 values) than for less toxic compounds.
在大鼠中研究了内源性羧酸酯酶（CaE）对多种有机磷（OP）化合物致死作用的防护能力。通过比较对照大鼠和皮下注射2 mg/kg的2-（O-甲酚基）-4H-1,3,2-苯并二氧磷杂环己二烯-2-氧化物以抑制其CaE活性的大鼠体内OP化合物的半数致死剂量（LD50）值的差异，来测定内源性CaE提供的体内防护作用。内源性CaE对梭曼、沙林、塔崩和对氧磷的体内毒性具有显著的防护作用，但对敌敌畏、二异丙基氟磷酸酯或乙氧甲基-S-[2-（二异丙基氨基）乙基]硫代磷酸酯（VX）则没有防护作用。通过测量血浆CaE和脑乙酰胆碱酯酶（AChE）抑制的体外双分子速率常数（ki），评估了体内CaE对OP化合物的防护作用与其与CaE和AChE的相对反应活性之间的关系。除VX外，CaE抑制的ki值变化小于10倍，而AChE抑制的ki值变化达10⁵倍。随着CaE/AChE ki比值的增加，等毒性剂量的OP化合物对CaE的体内抑制程度增加。然而，对照大鼠与CaE抑制大鼠的LD50值的防护比值随着CaE/AChE ki比值的增加而降低。体内CaE防护作用与CaE相对体外反应活性之间的这种反比关系表明，CaE解毒作用对于高毒性OP化合物（即具有高AChE ki值和低LD50值的化合物）比对于低毒性化合物更为重要。
