کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2598617 | 1133140 | 2015 | 12 صفحه PDF | دانلود رایگان |
• Elimination kinetics of GF by 6-OxP-CD in vitro was dependent on the respective concentration ratios.
• Elimination of GF enantiomers was strongly stereoselective with preference for the more toxic (−)-GF.
• Evidence was found for the existence of inclusion complexes between substituted cyclodextrin and GF.
• Covalent CHMP-6-OxP-CD conjugates were instable and decomposed into small molecular fragments.
• Fragmentation experiments of different species proved participation of the oximate substituent of 6-OxP-CD in efficient GF detoxification.
• A reaction scheme of the possible interactions of GF with 6-OxP-CD was developed.
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)n-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.
Journal: Toxicology Letters - Volume 239, Issue 1, 19 November 2015, Pages 41–52