Title: Reactivation and aging kinetics of human acetylcholinesterase inhibited by organophosphonylcholines Worek F, Thiermann H, Szinicz L Ref: Archives of Toxicology, 78:212, 2004 : PubMed
A great number of structurally different organophosphorus compounds (OPs) was synthesized in the past decades to be used as pesticides or chemical warfare agents. Methyl-fluorophosphonylcholines were found to be highly toxic OPs and the acetylcholinesterase (AChE) reactivator pralidoxime was shown to be unable to reactivate inhibited AChE. In the course of the development of more effective AChE reactivators, we have determined the reactivation rate constants of various oximes with human AChE inhibited by methylfluorophosphonylcholine (MFPCh), methylfluoro-beta-phosphonylcholine (MFP beta Ch) and methylfluorophosphonylhomocholine (MFPhCh). In addition, we investigated the potential influence of aging phenomena on the oxime efficacy. Human AChE inhibited by MFPCh, MFP beta Ch or MFPhCh was extremely resistant towards reactivation by oximes. Nevertheless, the newer compounds, HLo 7 and HI 6, were substantially more potent reactivators than obidoxime and pralidoxime. The low oxime efficacy was not due to rapid aging since no decrease in reactivatability was found over 96 h at 37 degrees C. Within this period a substantial spontaneous reactivation was observed, with MFPCh >MFP beta Ch >MFPhCh, which did not follow pseudo-first-order kinetics. In conclusion, the unexpected results, i.e., high resistance of inhibited AChE towards oxime reactivation and aging, and much lower resistance towards spontaneous reactivation, calls for further experiments at a molecular level for a better understanding of the interactions among AChE, its inhibitors and reactivators.
Worek F, Thiermann H, Szinicz L (2004) Reactivation and aging kinetics of human acetylcholinesterase inhibited by organophosphonylcholines Archives of Toxicology78: 212-7
Worek F, Thiermann H, Szinicz L (2004) Archives of Toxicology78: 212-7
