Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro
article
Detoxification mechanisms of the chemical warfare agent cyclosarin (GF) in presence of 6-OxP-CD were investigated in detail in in vitro model systems. Most important finding was the preference of 6-Ox-P-CD to eliminate the more toxic (-)-GF. However, elimination of GF enantiomers was dependent on the 6-OxP-CD:GF ratios showing decreasing stereoselectivity and speed of the reaction with increasing GF concentrations. Formation of covalent mono, bis, tris and tetrakis conjugates ((CHMP)<inf>n</inf>-6-OxP-CD) and appearance of small molecular fragments (SMF) as possible decomposition products after consumption of 6-OxP-CD could be observed.. Interestingly, the non-toxic metabolite O-cyclohexyl methylphosphonic acid (CHMPA) and covalent mono and bis conjugates of 6-OxP-CD and GF were immediately formed, indicating that GF elimination proceeds along different pathways. These important new insights provide information about the mode of action of 6-Ox-P-CD including the role of the pyridinium aldoxime group on the cyclodextrin ring. They are the basis for further investigations in biological media, which could eventually lead to approval of 6-OxP-CD as a new antidote against nerve agent toxicity. © 2015 Elsevier Ireland Ltd.
Topics
TNO Identifier
528228
ISSN
0378-4274
Source
Toxicology Letters, 239(1), pp. 41-52.
Publisher
Elsevier Ireland Ltd
Pages
41-52
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