Oxime-induced reactivation of acetylcholinesterase inhibited by organophosphinates

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Abstract
The comparative potency of oximes for reactivation of inhibited eel acetylcholinesterase (AChE) in vitro is dependent on the organophosphinate inhibitor. Some of the data, dealing with a reference organophosphonate, support the conclusion of other investigators that the oxime potency order is also dependent on the inhibiting phosphonate. This work was done to identify more clearly the nature of phosphinylated AChE with regard to oxime reactivation potency and the potential of phosphinates as pretreatment drugs to protect AChE against organophosphonate poisoning. We have determined the reactivation potency of four oximes—2‐PAM, HI‐6, TMB‐4 and toxogonin—against four phosphinates—4‐nitrophenyl methyl(phenyl)phosphinate (PMP), 4‐nitrophenyl chloromethyl(phenyl)phosphinate (CPMP), 4‐nitrophenyl trifluoromethyl(phenyl) phosphinate and 4‐nitrophenyl bis(2‐thienyl)phosphinate. For comparison, the phosphonate sarin (GB, isopropyl methylphosphonofluoridate) was included. Incubation of the inhibited enzyme (I‐AChE) at 25°C was with 0.30 μM oxime for PMP, 3.0 μM oxime for sarin and CPMP and 100 μM oxime for the two remaining phosphinates. AChE activity was assayed spectrophotometrically for 3.0 min at 272.5 nm at 25°C in 0.10 M MOPS buffer (pH 7.60) using phenyl acetate as substrate. When sarin was the inhibitor (0% spontaneous recovery after a 2‐h incubation), the order of oxime reactivation was 2‐PAM (46%) ⩾ toxogonin (33%) = TMB‐4 (31%) > HI‐6 (9%) after 2‐h incubations. For PMP (12% spontaneous recovery after a 2‐h incubation) the oxime order was toxogonin (67%) > TMB‐4 (53%) > 2‐PAM (40%) after 2‐h incubations. For CPMP (8% spontaneous recovery after a 30‐min incubation) the order was toxogonin (65%) = TMB‐4 (59%) = HI‐6 (57%) > 2‐PAM (12%) after 30‐min incubations. For the trifluorophosphinate the order was toxogonin (18%) = TMB‐4 (17%) > HI‐6 (12%) ⩾ 2‐PAM (3%) after 5‐min incubations. For the bis‐thienylphosphinate the order was HI‐6 (38%) > 2‐PAM (20%) > TMB‐4 (0.4%) > toxogonin (0%) after 5‐min incubations. Despite some uncertainty in the oxime orders, these results support the conclusion that oxime potency is dependent on the organophosphinate used as the AChE inhibitor. The results also broaden the database that underpins the generally accepted conclusion, that for a given oxime its reactivation potency is dependent on the organophosphorous compound used to inhibit AChE.

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