Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation, and aging kinetics

Human poisoning by organophosphates bearing two methoxy groups, e.g. by mal athion, paraoxon-methyl, dimethoate and oxydemeton-methyl, is generally con sidered to be rather resistant to oxime therapy. Since the oxime effectiven ess is influenced not only by its reactivating potential but also by inhibi tion, aging and spontaneous reactivation kinetics, experiments were perform ed with human acetyl- (AChE) and butyrylcholinesterase (BChE) to determine the respective kinetic constants. The efficacy of obidoxime in reactivating dimethylphosphoryl-AChE was 40, 9 and 3 times higher than of HI 6, pralido xime and HLo 7, respectively. Aging (t(1/2) 3.7 h) and spontaneous reactiva tion (t(1/2) 0.7 h) occurred concomitantly, with the portion of the aged en zyme being dependent on the presence of excess inhibitor. Calculation of st eady-state AChE activity in the presence of inhibitor and oxime revealed th at obidoxime was superior to pralidoxime. In addition, organophosphate conc entrations up to 10(-6) M (paraoxon-methyl) and 10(-4) M (oxydemeton-methyl ) could be counteracted at clinically relevant oxime concentrations (10 mu M). These data indicate that oximes may effectively reactivate human dimeth ylphosphoryl-AChE. Failure of oximes may be attributed to megadose intoxica tions and to prolonged time intervals between poison uptake and oxime admin istration. The potency of the oximes to reactivate dimethylphosphoryl-BChE was much lower and the spontaneous reactivation slower (t1/2 9 h), while ag ing proceeded at a comparable rate. Thus, BChE activity determination for d iagnosis and therapeutic monitoring may give no reliable information on ACh E status.