Investigation of Multiple Mechanisms for Potentiation of Malaoxon's Anticholinesterase Action by Triorthotolyl Phosphate 1

Abstract

Summary

The degree of potentiation of malaoxon toxicity by 10 to 50 mg/kg of TOTP was associated with its inhibition of mouse liver carboxylesterase activity; however, the degree of potentiation increased with increasing dose of TOTP beyond the dose which caused maximal inhibition of liver carboxylesterase activity. TOTP did not alter the sensitivity of mouse brain cholinesterase to inhibition by malaoxon. As the pretreatment dose of TOTP was increased from 50 to 125 mg/kg there was an associated increase of inhibition of malaoxon binding by liver and increase in the inhibition of liver cholinesterase activity. These findings indicate that the increase in malaoxon potentiation beyond that detected at maximum inhibition of liver carboxylesterase activities by TOTP may result from increased inhibition of malaoxon binding. It appears that both carboxylesterases and cholinesterases may contribute to malaoxon binding by mouse liver. and that binding to liver cholinesterases may become the most important mechanism of inactivation of malaoxon when carboxylesterases are completely inhibited.