Oxidative bioactivation of S-alkyl phosphorothiolate pesticides: stereospecificity of profenofos insecticide activation

• Published in: Science (American Association for the Advancement of Science) Vol. 219; no. 4580; pp. 63 - 65
• Main Authors: Wing, Keith D., Glickman, Andrew H., Casida, John E.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.01.1983; American Association for the Advancement of Science
• Subjects: Animals; Biochemistry; Cholinesterase Inhibitors - metabolism; In Vitro Techniques; Insecticides; Insecticides - metabolism; Isomers; Mice; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; Organothiophosphates - metabolism; Organothiophosphorus Compounds - metabolism; Oxidases; Oxidation; Oxidation-Reduction; Pain; Pesticides; Physiological aspects; Piperonyl Butoxide - pharmacology; Standard deviation; Stereoisomerism; Toxicity
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.6849116

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.