Author:
Pressly Brandon,Vasylieva Natalia,Barnych Bogdan,Singh Vikrant,Singh Latika,Bruun Donald A.,Hwang Sung Hee,Chen Yi-Je,Fettinger James C.,Johnnides Stephanie,Lein Pamela J.,Yang Jun,Hammock Bruce D.,Wulff Heike
Abstract
AbstractAcute intoxication with picrotoxin or the rodenticide tetramethylenedisulfotetramine (TETS) can cause seizures that rapidly progress to status epilepticus and death. Both compounds inhibit γ-aminobutyric acid type-A (GABAA) receptors with similar potency. However, TETS is approximately 100 × more lethal than picrotoxin. Here, we directly compared the toxicokinetics of the two compounds following intraperitoneal administration in mice. Using LC/MS analysis we found that picrotoxinin, the active component of picrotoxin, hydrolyses quickly into picrotoxic acid, has a short in vivo half-life, and is moderately brain penetrant (brain/plasma ratio 0.3). TETS, in contrast, is not metabolized by liver microsomes and persists in the body following intoxication. Using both GC/MS and a TETS-selective immunoassay we found that mice administered TETS at the LD50 of 0.2 mg/kg in the presence of rescue medications exhibited serum levels that remained constant around 1.6 μM for 48 h before falling slowly over the next 10 days. TETS showed a similar persistence in tissues. Whole-cell patch-clamp demonstrated that brain and serum extracts prepared from mice at 2 and 14 days after TETS administration significantly blocked heterologously expressed α2β3γ2 GABAA-receptors confirming that TETS remains pharmacodynamically active in vivo. This observed persistence may contribute to the long-lasting and recurrent seizures observed following human exposures. We suggest that countermeasures to neutralize TETS or accelerate its elimination should be explored for this highly dangerous threat agent.
Funder
National Institute of Neurological Disorders and Stroke
National Institute of Environmental Health Sciences
National Institute of General Medical Sciences
Publisher
Springer Science and Business Media LLC
Subject
Health, Toxicology and Mutagenesis,Toxicology,General Medicine
Cited by
11 articles.
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