The Phosphorothioic Acid O-(2-Chloro-2,3,3-Trifluorocyclobutyl) O-Ethyl S-Propyl Ester Exacerbates Organophosphate Polyneuropathy Without Inhibition of Neuropathy Target Esterase

Abstract

Organophosphate-induced delayed polyneuropathy (OPIDP) is thought to be initiated by a variety of neuropathy target esterase (NTE) inhibitors. However, certain inhibitors such as phenylmethanesulfonyl fluoride, phenyl N-methyl N-benzyl carbamate, and phenyl di-n-pentyl phosphinate protect from OPIDP when given to hens before organophosphorus esters. They protect from neuropathy by preventing the binding of neuropathic inhibitors to NTE catalytic site. In contrast, when such NTE inhibitors are given afterward, the resulting clinical effect is more severe. This phenomenon was called promotion of OPIDP. Promotion has been tentatively explained by the interaction of promoters with a target other than the catalytic center of NTE. However, the doses of promoters which cause the effect have, so far, been found to always be inhibitory of NTE. We report that the phosphorothioic acid O-(2-chloro-2,3,3-trifluoro-cyclobutyl) O-ethyl S-propyl ester (KBR-2822) given to hens at doses which did not inhibit NTE (2.5 mg/kg po) promoted the neuropathies initiated by either dibutyl-2,2-dichlorovinyl phosphate (DBDCVP, 0.4 mg/kg sc, 24 hr earlier) or diisopropyl phosphorofluoridate (DFP, 0.3 mg/kg sc or 0.5 mg/kg sc, 24 hr earlier). When given alone, DBDCVP and DFP (0.5 mg/kg) caused mild OPIDP, whereas the lower dose of DFP did not cause clinical effects. Dose-response relationships with KBR-2822 indicated that clinical effects of the combined treatments are unlikely to be additive because the compound did not cause OPIDP up to the maximum tolerated dose (10 mg/kg po). Promotion also occurred when KBR-2822 (2.5 mg/kg po) was given before either DBDCVP (0.4 mg/kg sc) or DFP (0.3 mg/kg sc). NTE inhibitions in the nervous tissues caused by DBDCVP or DFP were not affected by pretreatment with KBR-2822, suggesting that the delivery of neuropathic NTE inhibitors was not modified. We conclude that KBR-2822 promotes OPIDP initiated by either DBDCVP or DFP by affecting a target other than NTE catalytic site.