Effect of human plasma on the reactivation of sarin-inhibited human erythrocyte acetylcholinesterase.
The reactivation of organophosphate-inhibited acetylcholinesterase (AChE) by oximes inevitably results in the formation of highly reactive phosphoryloximes (POX), which are able to re-inhibit the enzyme. In this study, the dependence of POX formation on AChE concentration was investigated with sarin-inhibited human erythrocyte AChE (EryAChE). A marked dependence was found with obidoxime but not with the experimental oxime HI 6, suggesting great differences in the decomposition rates of the respective POXs. At a physiological erythrocyte content the reactivation of EryAChE was markedly affected by POX with obidoxime and pralidoxime (2-PAM) but not with the newer oximes HI 6 and HLö 7. Addition of extensively dialysed, sarin-treated human plasma reduced the reactivation by obidoxime and 2-PAM even more. Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE). This effect was pronounced in diluted plasma, but was obscured in concentrated plasma, probably because of re-inhibition by the generated POX. Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE. The results indicate that obidoxime and 2-PAM may reactivate sarin-inhibited AChE insufficiently due to re-inhibition by the POX formed. In addition, the re-inhibition of Ery-AChE may be aggravated by the POX that is produced during BChE reactivation. These reactions must be regarded as therapeutically detrimental and disqualify those oximes which are capable of forming stable POX by reactivation of BChE.
Worek
F
F
Sanitätsakademie der Bundeswehr, Institut für Pharmakologie und Toxikologie, Garching, Germany.
Eyer
P
P
Kiderlen
D
D
Thiermann
H
H
Szinicz
L
L
D000110:Acetylcholinesterase / Q000097:blood*; D002091:Butyrylcholinesterase / Q000097:blood; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004905:Erythrocyte Aging / Q000187:drug effects / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D009768:Obidoxime Chloride / Q000494:pharmacology; D010091:Oximes; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012524:Sarin / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D011725:Pyridines; D011726:Pyridinium Compounds; C058577:HLo 7; D009768:Obidoxime Chloride; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime