Activation and Detoxication of <i>S</i>-Alkyl Phosphorothiolate Insecticides

Abstract

Prothiophos oxon (S-propyl form) and its S-methyl, ethyl and butyl homologs were poor in vitro inhibitors of acetylcholinesterase (AChE), but the S-propyl and butyl oxons were highly insecticidal to houseflies, and inhibited ACNE in vivo. Evidence indicates that such 5alkyl oxons are converted to unstable intermediates by mixed function oxidase system, which have been oxidized on the sulfur and are more reactive with AChE in the case of the S-propyl and butyl oxons, when more hydrolyzable in the case of the S-methyl and ethyl oxons.

Oxidative Glutathione Conjugation and Its Novel Role in Activation of the Organophosphorus Insecticide Prothiofos

“…As to S-oxide, the sulfur atom-phosphorus atom bond in Soxide is 2.36 Å, in both the (R)p and (S)p configurations, which is wide and quite unstable, 3,6) thus it may cause PrS(O) to be easily displaced by GS Ϫ . Moreover, the fact that the alkyl or aryl group in the OP compound is pulled by GST and conjugated into GSH is proven by drug metabolism.…”

“…Among S-alkylphosphorothiolate-type OP insecticides, such as methamidophos, 1) profenofos [2][3][4] and TIA-230 (pyraclofos), 5) there are those, despite having an oxon structure, that do not inhibit AChE but are further oxidized into the S-oxide, only then, showing insecticidal activity by inhibiting AChE. Prothiofos, 6) too, is a specific OP insecticide in that prothiofos oxon (oxon) is oxidized into prothiofos oxon S-oxide (Soxide) and then inhibits AChE. Prothiofos has as much insecticidal activity in OP resistant insect strains as in susceptible strains if not more, and its activity has so far not been counteracted by resistance.…”

Insecticide metabolism and selective toxicity

“…In such compounds, which show generally favourable mammalian toxicity, the nature of the aryl substituents is frequently less critical than for corresponding 0,O-diethyl phosphates (Drabek and Fluck 1979), and they tend also to be effective against OP-resistant strains of insects (Drabek and Fluck 1979, Hirashama et al 1984, Kimura et al 1984. For example, prothiophos oxon (9) and its S-methyl, S-ethyl and S-n-butyl analogues were poor inhibitors of AChE, but (9) and its S-n-butyl homologue were highly insecticidal, especially towards OPresistant houseflies (Kimura et al 1984). T h e S-propyl and S-n-butyl, although not the S-methyl and S-ethyl oxons, were converted into more potent inhibitors by ratliver microsomes ( + NADPH); sulphoxides of the first two oxons are better leaving groups for interaction with AChE than 2,4-dichlorophenol, whereas those arising from the smaller alkvlthio groups appear to be deactivated by rapid hydrolysis.…”