Biomarkers of organophosphorus nerve agent exposure: comparison of phosphylated butyrylcholinesterase and phosphylated albumin after oxime therapy.
Organophosphorus nerve agents inhibit the activity of cholinesterases by phosphylation of the active site serine. In addition, sarin, cyclosarin, soman and tabun have been shown to phosphylate a tyrosine residue in albumin. Therapies against nerve agent poisoning include the use of oximes to reactivate inhibited cholinesterases by displacement of the phosphyl moiety and hence detectable levels of adducts with cholinesterases may be reduced. Adducts with tyrosine have been shown to be persistent in the guinea pig in the presence of oxime therapy. Plasma samples obtained from an animal study aimed at improving therapy against nerve agent poisoning were used to compare the suitability of tyrosine and butyrylcholinesterase (BuChE) adducts as biomarkers of nerve agent exposure after treatment with therapeutic oximes. Under the terms of the project licence, these samples could be collected only on death of the animal, which occurred within hours of exposure or when culled at 23 or 24 days. Tyrosine adducts were detected in all samples collected following intra-muscular administration of twice the LD50 dose of the respective nerve agent. Aged BuChE adducts were detected in samples collected within a few hours after administration of soman and tabun, but not after 23 or 24 days. No BuChE adducts were detected in animals exposed to sarin and cyclosarin where samples were collected only after 23 or 24 days.
Read
Robert W
RW
Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire, SP4 0JQ, UK. rwread@dstl.gov.uk
Riches
James R
JR
Stevens
Jacqueline A
JA
Stubbs
Sarah J
SJ
Black
Robin M
RM
D000818:Animals; D015415:Biomarkers; D002091:Butyrylcholinesterase / Q000032:analysis / Q000737:chemistry*; D002143:Callitrichinae; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D004781:Environmental Exposure; D006801:Humans; D007273:Injections, Intramuscular; D007928:Lethal Dose 50; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*; D010091:Oximes / Q000627:therapeutic use*; D010766:Phosphorylation; D012709:Serum Albumin / Q000032:analysis / Q000737:chemistry*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D015415:Biomarkers; D002491:Central Nervous System Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D012709:Serum Albumin; D014443:Tyrosine; D002091:Butyrylcholinesterase