INHIBITION, REACTIVATION AND AGING KINETICS OF CYCLOHEXYLMETHYLPHOSPHONOFLUORIDATE-INHIBITED HUMAN CHOLINESTERASES

Cyclohexylmethylphosphonofluoridate (cyclosarin) is a highly toxic org anophosphate, which was shown to be rather resistant to conventional o xime therapy. To give more insight into the inhibition, reactivation a nd aging kinetics, human acetyl-(AChE) and butyrylcholinesterase (BChE ) were inhibited by cyclosarin (k(2) Of 7.4 and 3.8 10(8) M-1 min(-1) , respectively; pH 7.4, 37 degrees C) and reactivated with obidoxime, pralidoxime and three experimental oximes. The new oxime HLo 7 o]-meth oxy]-methyl]-2,4-bis-[(hydroxyimino)methyl] pyridinium dimethanesulpho nate) was shown to be superior to the other oximes. At oxime concentra tions anticipated to be relevant in humans, obidoxime and pralidoxime were extremely weak reactivators of AChE. Aging velocity of BChE was a lmost fourfold higher compared to AChE (k(a) of 0.32 h(-1) and 0.08 h( -1), respectively). A substantial spontaneous reactivation was observe d with AChE These results support previous in vivo findings that obido xime and pralidoxime are insufficient antidotes in cyclosarin poisonin g. By contrast, HLo 7 was shown to be an extremely potent reactivator of human AChE and BChE, which supports its position as a broad-spectru m oxime.