Article

An In Vitro Comparative Study on the Reactivation of Nerve Agent-Inhibited Guinea Pig and Human Acetylcholinesterases by Oximes

Department of Molecular Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
Biochemistry (Impact Factor: 3.02). 11/2007; 46(42):11771-9. DOI: 10.1021/bi701002f
Source: PubMed

ABSTRACT

The reactivation of nerve agent-inhibited acetylcholinesterase (AChE) by oxime is the most important step in the treatment of nerve agent poisoning. Since the evaluation of nerve agent antidotes cannot be conducted in humans, results from animal experiments are extrapolated to humans. Guinea pig is one of the animal models that is frequently used for conducting nerve agent antidote evaluations. Several investigations have demonstrated that the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited AChE. If the in vitro oxime reactivation of nerve agent-inhibited animal AChE is similar to that of human AChE, it is likely that the results of an in vivo animal study will reliably extrapolate to humans. Therefore, the goal of this study was to compare the reactivation of guinea pig and human AChEs inhibited by six different G and V type nerve agents. Reactivation kinetic studies with five mono- and bis-pyridinium oximes showed that oxime reactivation of nerve agent-inhibited human AChE in most cases was faster than guinea pig AChE. The most significant enhancement was observed in the reactivation of human AChE inhibited by nerve agents containing bulky side chains GF, GD, and VR, by H-series oximes HLo-7, HI-6, and ICD-585. In these cases, species-related differences observed between the two AChEs, based on the second-order reactivation rate constants, were 90- to over 400-fold. On the other hand, less than 3-fold differences were observed in the rates of aging of nerve agent-inhibited guinea pig and human AChEs. These results suggest that the remarkable species-related differences observed in the reactivation of nerve agent-inhibited guinea pig and human AChEs were not due to differences in the rates of aging. These results also suggest that guinea pig may not be an appropriate animal model for the in vivo evaluation of oxime therapy.

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    • "In a recent study, we demonstrated that species-related variations in oxime reactivation between guinea pig AChE and recombinant human AChE (rHu AChE) were especially pronounced with nerve agents containing bulky side-chains such as GF, GD, and VR when H-series oximes (HI-6 and HLo-7) were used as reactivators. In these cases, the reactivation of guinea pig AChE was 180-to 430-fold slower than rHu AChE [20]. Since guinea pig is frequently used as an animal model for the evaluation of nerve agent antidotes, it raises a concern regarding the suitability of this animal model for predicting the efficacy of oximes in humans. "
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