The specificity of carboxylesterase protection against the toxicity of organophosphorus compounds

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Abstract

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 <10-fold while ki values for AChE inhibition varied 105-fold. The degree of in vivo inhibition of CaE by equitoxic doses of the OP compounds increased as the CaEAChE ki ratio increased. However, the protective ratio of the LD50 values in control vs CaE-inhibited rats decreased as the CaEAChE 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.

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The opinions or assertions contained herein are the personal views of the author and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. In conducting the research described in this report, the investigator adhered to the Guide for the Care and Use of Laboratory Animals, National Institutes of Health Publication 85-23.

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