Relationship between acute toxicity and in vitro inhibition and hydrolysis of a series of carbalkoxy homologs of malathion

Abstract

A series of carbalkoxy homologs of malathion and malaoxon was prepared in which the dicarbalkoxy groups were varied from methyl to butyl. The acute oral toxicities of these compounds were determined using male Wistar rats, and it was found that the toxicities decreased with an increase in chain length. Inhibiting carboxylesterase in vivo with tri- o-tolyl phosphate (TOCP) demonstrated that both the malathion and malaoxon homologs were substrates for carboxylesterase, and that carboxylesterase was important in the detoxication of both malathion and malaoxon. In vitro studies with rat liver carboxylesterase and the malathion homologs as substrates showed that the K m values decreased with an increase in chain length, whereas the V max values increased with an increase in chain length. The in vitro findings indicated that the carboxylesterase had the greatest hydrolytic activity toward the carb- n-butoxy group of malathion followed by n-propyl, ethyl, isopropyl, and methyl homologs. The inhibition studies showed the bimolecular rate constant to decrease with an increase in chain length with erythrocyte cholinesterase and a reverse trend with carboxylesterase and serum cholinesterase. The in vivo toxicity was found to correlate with the in vitro enzymatic detoxication and inhibition patterns.