In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl-fluorophosphate

✍ Scribed by D. E. Lorke; M. Y. Hasan; K. Arafat; K. Kuča; K. Musilek; A. Schmitt; G. A. Petroianu

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 350 KB
• Volume: 28
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/jat.1344

✦ Synopsis

Oximes are enzyme reactivators used in treating poisoning with organophosphorus cholinesterase (AChE) inhibitors. The oxime dose which can be safely administered is limited by the intrinsic toxicity of the substances such as their own AChE-inhibiting tendency. Clinical experience with the available oximes is disappointing. To meet this need, new AChE reactivators of potential clinical utility have been developed. The purpose of the study was to estimate in vitro both the intrinsic toxicity and the extent of possible protection conferred by established (pralidoxime, obidoxime, HI-6, methoxime, trimedoxime) and experimental (K-type) oximes, using diisopropyl-fluoro-phosphate (DFP) as an AChE inhibitor. The IC 50 of DFP against human red blood cell AChE was determined (~120 nM). Measurements were then repeated in the presence of increasing oxime concentrations, leading to an apparent increase in DFP IC 50 . Calculated IC 50 values were plotted against oxime concentrations to obtain an IC 50 shift curve. The slope of this shift curve (tanα α α α α) was used to quantify the magnitude of the protective effect (nM IC 50 increase per μ μ μ μ μM oxime). We show that, in the case of a linear relationship between oxime concentration and IC 50 , the binding constant K, determined using the Schild equation, equals IC 50/DFP /tanα α α α α . Based on the values of tanα α α α α and of the binding constant K, some of the new K-oxime reactivators are far superior to pralidoxime (tanα α α α α = = = = = 0.8), obidoxime (1.5), HI-6 (0.8), trimedoxime (2.9) and methoxime (5.9), with K-107 (17), K-108 (20), and K-113 (16) being the outstanding compounds.