The specificity of carboxylesterase protection against the toxicity of organophosphorus compounds

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 LD 50 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)-4 H-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 ( k i ) for inhibition of plasma CaE and brain AChE. Except for VX, k i values for CaE inhibition varied <10-fold while k i 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 k i ratio increased. However, the protective ratio of the LD 50 values in control vs CaE-inhibited rats decreased as the CaE AChE k i 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 k i values and low LD 50 values) than for less toxic compounds.