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
Department of Pharmacology, Genome and Biomedical Sciences Facility, University of California, Room 3502, 451 Health Sciences Drive, Davis, CA, 95616, USA.
Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
Arch Toxicol. 2020 Jun;94(6):1995-2007. doi: 10.1007/s00204-020-02728-z. Epub 2020 Apr 1.
Acute 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 (GABA) 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 LD 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 αβγ GABA-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.
印防己毒素或灭鼠剂毒鼠强（TETS）急性中毒可引发癫痫发作，并迅速进展为癫痫持续状态，最终导致死亡。这两种化合物对γ-氨基丁酸A型（GABA）受体的抑制效力相似。然而，TETS的致死性约为印防己毒素的100倍。在此，我们直接比较了这两种化合物腹腔注射给小鼠后的毒代动力学。通过液相色谱/质谱分析，我们发现印防己毒素的活性成分印防己毒素宁迅速水解为印防己毒素酸，其体内半衰期较短，且脑渗透性中等（脑/血浆比值为0.3）。相比之下，TETS不会被肝微粒体代谢，中毒后会在体内持续存在。通过气相色谱/质谱分析和TETS选择性免疫测定，我们发现，在有抢救药物的情况下，以0.2 mg/kg的半数致死量给小鼠注射TETS后，其血清水平在48小时内保持在1.6 μM左右恒定，随后在接下来的10天内缓慢下降。TETS在组织中也表现出类似的持续性。全细胞膜片钳实验表明，在TETS给药后2天和14天从小鼠制备的脑和血清提取物能显著阻断异源表达的αβγ GABA受体，这证实TETS在体内仍具有药效学活性。观察到的这种持续性可能导致人类接触TETS后出现持久且反复发作的癫痫。我们建议，对于这种高度危险的威胁制剂，应探索中和TETS或加速其清除的对策。
