Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: Supersensitivity of acetylcholinesterase knockout mouse to VX lethality

The possibility that organophosphate toxicity is due to inhibition of targe ts other than acetylcholinesterase (AChE, EC 3.1.1.7) was examined in AChE knockout mice. Mice (34-55 days old) were grouped for this study, after it was determined that AChE, butyrylcholinesterase (BChE), and carboxylesteras e activities had reached stable values by this age. Mice with 0, 50, or 100 % AChE activity were treated subcutaneously with the nerve agent VX. The LD 50 for VX was 10 to 12 mug/kg in AChE-/-, 17 mug/kg in AChE+/-, and 24 mug/ kg in AChE+/+ mice. The same cholinergic signs of toxicity were present in AChE-/- mice as in wild-type mice, even though AChE-/- mice have no AChE wh ose inhibition could lead to cholinergic signs. Wild-type mice, but not ACh E-/- mice, were protected by pretreatment with atropine. Tissues were extra cted from VX-treated and untreated animals and tested for AChE, BChE, and a cylpeptide hydrolase activity. VX treatment inhibited 50% of the AChE activ ity in brain and muscle of AChE+/+ and +/-mice, 50% of the BChE activity in all three AChE genotypes, but did not significantly inhibit acylpeptide hy drolase activity. It was concluded that the toxicity of VX must be attribut ed to inhibition of nonacetylcholinesterase targets in the AChE-/- mouse. O rganophosphorus ester toxicity in wild-type mice is probably due to inhibit ion or binding to several proteins, only one of which is AChE.