Mechanism for potent reactivation ability of H oximes analyzed by reactivation kinetic studies with cholinesterases from different species.
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.
Luo
Chunyuan
C
Division of Bacterial and Rickettsial Diseases, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA. Chunyuan.luo@us.army.mil
Chambers
Carolyn
C
Yang
Yerie
Y
Saxena
Ashima
A
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D010755:Organophosphates / Q000737:chemistry / Q000633:toxicity; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*
D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase