Y. Ashani et al., COMBINED EFFECT OF ORGANOPHOSPHORUS HYDROLASE AND OXIME ON THE REACTIVATION RATE OF DIETHYLPHOSPHORYL-ACETYLCHOLINESTERASE CONJUGATES, Biochemical pharmacology, 55(2), 1998, pp. 159-168
Reactivation of inhibited acetylcholinesterase (AChE) is essential for
rapid recovery after organophosphate (OF) poisoning. However, followi
ng administration of an oxime reactivator, such as pralidoxime mesylat
e (P2S), in patients poisoned with certain diethylphosphorothioate pes
ticides, no reactivation is observed, presumably due to reinhibition b
y circulating anti-cholinesterase OPs. Pretreatment alone with organop
hosphorus hydrolases (OPH) that are capable of rapidly hydrolyzing OPs
was demonstrated, in animals, to confer significant protection agains
t OP toxicity. One strategy to augment the potentially therapeutic sco
pe of OPHs is a combined post-exposure treatment consisting of a drug(
s) commonly used against OP toxicity and a suitable hydrolase. In this
study, we examined the in vitro ability of OPH from Pseudomonas sp. (
OPHps) to prevent reinhibition of P2S-reactivated AChE by excess OPs.
The kinetic parameters of the reactivation of a series of diethylphosp
horyl-AChE (DEP-AChE) conjugates, obtained by the use of various dieth
ylphosphates, were determined and compared with the rates of reactivat
ion in the presence of OPHps, with and without the OP inhibitors in th
e reactivation medium. Extrapolation of the in vitro results to in viv
o conditions suggests that an OPHps concentration as low as 1 mu g/mL
blood would result in a 100-fold decrease in the concentration of circ
ulating anti-AChE pesticides within less than one blood-circulation ti
me, thereby minimizing reinhibition of the reactivated enzyme. Thus, f
or DEP-based pesticides, the combination of P2S-OPH treatment can sign
ificantly improve clinical recovery after OP intoxication. In addition
, it is shown here for the first time that an OPH can effectively hydr
olyze quaternary ammonium-containing OPs. This indicates that hydrolys
is oi phosphorylated oximes, toxic side products of oxime treatment, m
ay also be accelerated by OPHs. (C) 1998 Elsevier Science Inc.