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

• Published in: Chemico-biological interactions Vol. 187; no. 1; pp. 185 - 190
• Main Authors: Luo, Chunyuan, Chambers, Carolyn, Yang, Yerie, Saxena, Ashima
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 06.09.2010
• Subjects: Acetylcholinesterase - metabolism; Animals; Cattle; Chemical Warfare Agents - chemistry; Chemical Warfare Agents - toxicity; Cholinesterase Reactivators - chemistry; Cholinesterase Reactivators - pharmacology; Enzyme Activation - drug effects; Erythrocytes - enzymology; Guinea pig acetylcholinesterase; Guinea Pigs; H oxime; Human acetylcholinesterase; Humans; Kinetics; Nerve agent; Organophosphates - chemistry; Organophosphates - toxicity; Oximes - chemistry; Oximes - pharmacology; Reactivation mechanism; Rhesus monkey acetylcholinesterase; Human acetylcholinesterase; Rhesus monkey acetylcholinesterase; H oxime; Reactivation mechanism; Nerve agent; Guinea pig acetylcholinesterase
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2010.01.018

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.