Phosphorothiolate pesticides and related compounds: Oxidative bioactivation and aging of the inhibited acetylcholinesterase

Several phosphorothiolates with a C₂ to C₆ S-alkyl substituent (i.e., ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or cyclohexyl) undergo microsomal oxidase activation to more potent acetylcholinesterase (AChE) inhibitors. Profenofos is activated by both mouse liver and house fly abdomen microsomes. The phosphorothiolates examined having S-methyl, S-benzyl, S-phenyl, and a variety of other thiol substituents and the phosphoramidothiolates were not converted to more potent AChE inhibitors. The microsomal oxidese system cleaves (±)-profenofos predominantly at the P-S-propyl linkage probably via initial sulfoxidation. (−)-Profenofos and O,S-diethyl O-phenyl phosphorothioate undergo in vivo oxidative activation as evidenced by lessened chick brain AChE inhibition after pretreatment with piperonyl butoxide. AChE inhibited in vitro by several bioactivated phosphorothiolates quickly becomes refractory to oxime reactivation, i.e., it undergoes aging. Thus, the toxicological properties of some S-propyl, S-butyl, and related phosphorothiolates are determined in part by their bioactivation and AChE-aging reactions.