ABSTRACT
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 II. Stability of Cholinesterases (ChE) In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . 193
III. Scavenger Protection in Rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 IV. Prophylaxis against Soman Inhalation Toxicity in Guinea
Pigs with Human Butyrylcholinesterase (HuBChE). . . . . . . . . . . . . . . . . . . 195 V. Comparison of Antidote Protection against Soman
by Pyridostigmine, HI-6, and Acetylcholinesterase (AChE) . . . . . . . . . . . . 196 VI. Experiments with Non-Human Primates . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
VII. Improving the Bioscavenging Capability of ChE . . . . . . . . . . . . . . . . . . . . . 202 A. Amplification of the Effectiveness of ChE for Detoxification
of Organophosphates (OP) by Oximes . . . . . . . . . . . . . . . . . . . . . . . . . . 203 B. Site-Specific Mutagenesis of AChE . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 C. OP Hydrolyzing Enzymes, e.g., OPH, OPAA,
Paraoxonase, Parathion Hydrolase, etc. . . . . . . . . . . . . . . . . . . . . . . . . . 205 D. Carboxylesterase as a Bioscavenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 E. Huperzine A as a Pretreatment Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 F. Immobilized ChE for the Decontamination of OP . . . . . . . . . . . . . . . . . 208
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
The acute toxicity of organophosphorus (OP) compounds is usually attributed to their irreversible inhibition of acetylcholinesterase (AChE; EC 3.1.1.7).1,2 The resultant increase in the level of acetylcholine at cholinergic synapses, particularly in brain and
diaphragm, produces an acute cholinergic crisis characterized by miosis, increased tracheobronchial and salivary secretions, bronchoconstriction, bradycardia, fasciculation, behavioral incapacitation, muscular weakness, and convulsions culminating in death by respiratory failure.3 Current antidotal regimens for OP poisoning consist of a combination of pretreatment with a spontaneously reactivating AChE inhibitor such as pyridostigmine bromide to protect AChE from irreversible inhibition by OP compounds, postexposure therapy with anticholinergic drugs such as atropine sulfate to counteract the effects of excess acetylcholine, and oximes such as 2-PAM chloride to reactivate OP-inhibited AChE.4 Although these antidotal regimens are highly effective in preventing lethality of animals from OP poisoning, they do not prevent the post-exposure incapacitation, convulsions, performance deficits, or in many cases, permanent brain damage.5 –7 These symptoms are commonly observed in experimental animals and are likely to occur in humans. An anticonvulsant drug, diazepam, was included as a treatment to minimize convulsions, thereby minimizing the risk of permanent brain damage.7 The problems intrinsic to these antidotes stimulated attempts to develop a single protective drug devoid of pharmacological effects, which would provide protection against the lethality of OP and prevent post-exposure incapacitation.7
