Abstract:
:Human butyrylcholinesterase (E.C. 3.1.1.8) purified from blood plasma has previously been shown to provide protection against up to five and a half times the median lethal dose of an organophosphorus nerve agent in several animal models. In this study the stoichiometric nature of the protection afforded by human butyrylcholinesterase against organophosphorus nerve agents was investigated in guinea pigs. Animals were administered human butyrylcholinesterase (26.15 mg/kg ≡ 308 nmol/kg) by the intravascular or intramuscular route. Animals were subsequently dosed with either soman or VX in accordance with a stage-wise adaptive dose design to estimate the modified median lethal dose in treated animals. Human butyrylcholinesterase (308 nmol/kg) increased the median lethal dose of soman from 154 nmol/kg to 770 nmol/kg. Comparing the molar ratio of agent molecules to enzyme active sites yielded a stoichiometric protective ratio of 2:1 for soman, likely related to the similar stereoselectivity the enzyme has compared to the toxic target, acetylcholinesterase. In contrast, human butyrylcholinesterase (308 nmol/kg) increased the median lethal dose of VX from 30 nmol/kg to 312 nmol/kg, resulting in a stoichiometric protective ratio of only 1:1, suggesting a lack of stereoselectivity for this agent.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Cerasoli DM,Armstrong SJ,Reeves TE,Hodgins SM,Kasten SA,Lee-Stubbs RB,Cadieux CL,Otto TC,Capacio BR,Lenz DEdoi
10.1016/j.bcp.2019.113670subject
Has Abstractpub_date
2020-01-01 00:00:00pages
113670eissn
0006-2952issn
1873-2968pii
S0006-2952(19)30369-7journal_volume
171pub_type
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