The phosphoryl oxime-destroying activity of human plasma

The potential of obidoxime and other pyridinium-4-aldoximes to reactivate d imethyl- and diethylphosphorylated cholinesterases is markedly restricted b y the inevitable formation of rather stable phosphoryl oximes (POXs) with h igh anticholinesterase activity. This effect is hardly seen with very dilut e enzyme preparations, but becomes significant at physiological enzyme conc entrations. Human plasma with the butyrylcholinesterase irreversibly blocke d by soman was able to stimulate obidoxime-induced reactivation of concentr ated erythrocyte acetylcholinesterase (Ery-AChE) to the saline extent as wa s observed with a dilute preparation, suggesting phosphoryl oxime-destroyin g capacity. The inactivating factor, which was tentatively termed POX-hydro lase, had (1) a molecular weight of >100 kDa; (2) required Ca2+, which coul d not be substituted by Zn2+ or Mg2+ ; and (3) lost its catalytic activity reversibly ill the presence of ethylenediaminetetraacetic acid (EDTA). The enzyme activity varied widely (20-fold) among different subjects and did no t follow the activity pattern of human serum paraoxonase (PONI). Rabbit pla sma with its particularly high paraoxonase content showed only weak POX-hyd rolase activity. These data suggest POX-hydrolase to be a different entity. POX-hydrolase was most active with the putative phosphoryl-obidoxime from paraoxon-ethyl, less with the product from paraoxon-methyl and least with t hat from diisopropylfluorophosphate. The analogue TMB-4 reacted similarly t o obidoxime. The putative phosphonyl oximes arising by the reaction of obid oxime with nerve agents were apparently not cleaved. The variation in POX-h ydrolase activity may additionally contribute to the variable response to o xime therapy in patients with organophosphate insecticide poisoning.