L-lactate reduces in vitro the inhibition of butyrylcholinesterase (BChE) by paraoxon (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, Serendipitous observation led us to the hypothesis that lactate might attenuate some of the POX effects. In vitro effects of l actate on the inhibition of butyrylcholinesterase (BChE) by POX were assess ed in plasma of 12 healthy human volunteers. The determinations were repeat ed using different lactate and different POX concentrations. The BChE activ ity determinations were performed in the following settings: (i) baseline untreated plasma (BL); (ii) after addition of POX to plasma (pl+POX); (iii) after POX and plasma were incubated and then lactate was added (pl+PO X/lact); (iv) after addition of lactate to plasma (pl+lact); (v) after lactate and plasma were incubated and then POX was added (pl+lact /POX); (vi) after lactate and POX were incubated and then added to plasma (lact+PO X/pl). In the micro- and millimolar ranges, lactate is able to abolish in vitro th e inhibition of BChE by POX in human plasma when added to plasma prior to P OX or when incubated with POX prior to addition to plasma. Lactate added to plasma after POX has no protective effect. In a second set of experiments, the effect of lactate on BChE activity was determined. At high millimolar concentrations, lactate itself inhibits BChE to an extent comparable to POX . Lactate is a mixed inhibitor of BChE, being able to interfere with the en zyme-substrate complex (inhibition constant for the enzyme-inhibitor-substr ate complex K-I(EIS)' = 81 mM) and the enzyme (inhibition constant for the enzyme-inhibitor complex K-I(EI) = 26 mM). Copyright (C) 1999 John Wiley & Sons, Ltd.