L-lactate protects in vitro acetylcholinesterase (AChE) from inhibition byparaoxon (E 600)

Intoxication with the organophosphorus compound paraoxon (POX), an inhibito r of serine hydrolases, is frequent, Grimes are the only enzyme reactivator s clinically available, Recent work has shown that lactate is able to reduc e in vitro the POX effects on butyrylcholinesterase (BChE), Most of the acu te clinical symptoms, however, are caused by inhibition of acetylcholineste rase (AChE), Effects of lactate on the inhibition of AChE by POX were asses sed in vitro in plasma of 12 (six male, six female) healthy human volunteer s. The determinations were repeated using different lactate and different P OX concentrations. The AChE activity determinations were performed in the following settings: (BL) baseline (untreated plasma); (a) after addition of POX to plasma (pl POX); (b) after POX and plasma were incubated and then lactate was added ( pl + POX/lact); (c) after addition of lactate to plasma (pl + lact); (d) af ter lactate and plasma were incubated and then POX was added (pl + lact/POX ); (e) after lactate and POX were incubated and then added to plasma (lact + POX/pl), In the micro- and millimolar ranges, lactate is able to protect in vitro AC hE from inhibition by POX when added to human plasma prior to POX or when i ncubated with POX prior to addition to plasma. Lactate added to plasma afte r POX has no protective effect. In a second set of experiments, the effect of lactate on AChE activity was determined. At high millimolar concentratio ns, lactate itself inhibits AChE non-competitively (mixed inhibition) to an extent comparable to POX (inhibition constant K-I = 254 mM), Copyright (C) 2000 John Wiley & Sons, Ltd.