Studies on pharmacokinetics of tetrodotoxin in the puffer fish and tetrodotoxin-transporter in the liver

河豚是河豚科鱼类，在肝脏和卵巢等特定组织中含有一种高效的神经毒素--河豚毒素(TTX)。然而，河豚中毒的潜在机制仍不清楚。本研究对河豚毒素单次给药的药代动力学进行了研究，结果表明河豚毒素可通过饱和机制从胃肠道吸收到体循环，并最终在肝脏中蓄积。体外平衡透析显示河豚毒素与血浆蛋白非特异性结合，主要以游离形式存在于河豚的循环血液中。此外，我们还利用抑制性消减杂交技术检测了肌肉注射TTX后河豚肝脏的基因表达谱。TTX的应用增加了肝脏中急性时相反应蛋白的基因表达以及与转运蛋白相关的基因。

Puffer fish, the family Tetraodontidae, contain a potent neurotoxin, tetrodotoxin (TTX) in high level in the specific tissues such as liver and ovary. However, the underlying mechanism of puffer fish toxification is still unclear. This study examined the pharmacokinetics of TTX in the puffer fish Takifugu rubripes by a single administration and demonstrated that TTX is absorbed into the systemic circulation from the gastrointestinal tract by saturable mechanism and finally accumulated in the liver. In vitro equilibrium dialysis revealed that TTX non-specifically binds to plasma proteins and exists predominately in the unbound form in the circulating blood of the puffer fish. Moreover, we examined hepatic gene expression profile of the puffer fish by suppression subtracted hybridization in response to the intramuscular administration of TTX. The administration of TTX increased the gene expression of the acute-phase response proteins in the liver as well as the genes related to transporters.