Mechanism for potent reactivation ability of H oximes analyzed by reactivation kinetic studies with cholinesterases from different species.

Abstract

Oxime-induced reactivation of organophosphorus (OP) nerve agent-inhibited acetylcholinesterase (AChE) is a very important step for the treatment of nerve agent toxicity. Therefore, extensive efforts are being made to develop more efficient and broad-spectrum oximes to replace the currently used oximes 2-PAM or obidoxime. In the 1970s and 1980s, several H oximes (such as HI-6 and HLo-7) were found to be very potent reactivators of non-aged soman-inhibited AChE. Later these oximes were shown to rapidly reactivate GF- and VR-inhibited AChE as well. However, the mechanism for the high potency of these H oximes is still unknown. In this study, the relationship between the reactivation rate constant of nerve agent-inhibited rhesus monkey AChE, human AChE and guinea pig AChE and the size of the alkoxyl (OR) group of nerve agents was analyzed. Results demonstrate that for nerve agent-inhibited rhesus monkey and human AChEs, reactivation by H oximes accelerated as the size of the OR group was increased. But with guinea pig AChE, reactivation by H oximes declined as the size of the OR group was increased. Reactivation kinetic study using GF- and VR-inhibited wild-type and mutant bovine AChEs has shown that mutations of Y124Q and W286A particularly reduced reactivation by these H oximes. Since these 2 amino acid residues are highly conserved in all AChEs sequenced to date, it is unlikely that the remarkable reduction observed in H oxime reactivation with guinea pig AChE is caused by a change in these two amino acid residues.

• Authors: Chunyuan Luo, Carolyn Chambers, Yerie Yang, Ashima Saxena
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 187 Issue 1-3 Pg. 185-90 (Sep 06 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 20096273 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• Chemical Warfare Agents
• Cholinesterase Reactivators
• Organophosphates
• Oximes
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Cattle
• Chemical Warfare Agents (chemistry, toxicity)
• Cholinesterase Reactivators (chemistry, pharmacology)
• Enzyme Activation (drug effects)
• Erythrocytes (enzymology)
• Guinea Pigs
• Humans
• Kinetics
• Organophosphates (chemistry, toxicity)
• Oximes (chemistry, pharmacology)