Oxidative Bioactivation of S -Alkyl Phosphorothiolate Pesticides: Stereospecificity of Profenofos Insecticide Activation

Abstract

The mouse liver microsomal mixed-function oxidase system converts several phosphorothiolate pesticides with S-ethyl, S-propyl, or S-butyl groups to more potent inhibitors of acetylcholinesterase. This activation is stereospecific for the chiral isomers of O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothiolate (profenofos insecticide); the more toxic (-) isomer becomes a 34-fold better inhibitor of acetylcholinesterase in vitro, whereas the less toxic (+) isomer is deactivated by a factor of 2. Prior treatment of the microsomes with piperonyl butoxide or another mixed-function oxidase inhibitor markedly decreases the activation. Piperonyl butoxide also protects against brain acetylcholinesterase inhibition and cholinergic symptoms in chicks resulting from (-)-profenofos administration, thus establishing the importance of the oxidative bioactivation of S-alkyl phosphorothiolate pesticides in vivo.

Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase

“…Methamidophos, however, contrary to other S-alkylphosphorothiolates, is not activated to more potent AChE inhibitors by mouse liver microsomes (Wing et al 1982) or by hen liver microsomes (our unpublished results).…”

Chirality of organophosphorus pesticides: Analysis and toxicity

“…This is due to the preferential sulfoxidation of (−)-profenofos in vivo, resulting in a metabolite that is up to 34 times more inhibitory to AChE Fosthiazate pk1 > pk2 > pk4 > pk3 CD and LPD Daphnia magna Acute toxicity; in vitro inhibition of electric eel acetylcholinesterase not stereoselective; has 4 stereoisomers due to presence of P and C chiral centers; stereoisomers identified based on elution order on Chiralpak ® AD column [35] Chloramidophos pk3 > pk2 > pk1 > pk4 CD Daphnia magna Acute toxicity; has 4 stereoisomers due to presence of P and C chiral centers; stereoisomers identified based on elution order on Chiralpak ® AD column [36] a CD: circular dichroism detector; LPD: laser polarimeter detector. [67]. The same study also showed the preferential detoxification of (+)-profenofos.…”

“…Like profenofos, methamidophos also contains a sulfur substituent to the chiral P in its structure, and may be subject to similar bioactivation processes as previously described here for profenofos [5,67] (Fig. 1).…”

Induction of microsomal cytochrome P450s by tire‐leachate compounds, habitat components of Aedes albopictus mosquito larvae

“…Esterases responsible for detoxification of temephos in this study may be inhibited by DEF with or without induction by BZT. Many phosphorothiolates, including DEF, can be converted to highly potent esterase inhibitors by P450 catalysis (Hur et al, 1992;Wing et al, 1983). If this is the case, BZT may induce P450s that carry out oxidative bioactivation of DEF.…”