Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, Fougères, 35306, France; BfR, German Federal Institute for Risk Assessment, Department of Food Safety, Max Dohrn Strasse 8-10, 10589, Berlin, Germany.
Analysis of Residues and Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, Fougères, 35306, France.
Toxicol Lett. 2019 Jun 1;307:17-25. doi: 10.1016/j.toxlet.2019.02.012. Epub 2019 Feb 27.
13-Desmethylspirolide C (13-SPX-C) is a phycotoxin produced by dinoflagellates which can accumulate in shellfish. 13-SPX-C induces neurotoxic effects in rodents through blockade of nicotinic acetylcholine receptors. As no human intoxication has been to date attributed to the consumption of 13-SPX-C-contaminated seafood, this toxin is not regulated according to the Codex Alimentarius. Nevertheless, shellfish consumers can be exposed to 13-SPX-C via shellfish consumption. In order to follow the fate of the toxin after ingestion and to verify whether metabolic detoxification could explain the lack of human intoxications, we assessed the metabolism of 13-SPX-C using several in vitro liver systems. First, both phase I and II reactions occurring with rat and human liver S9 fractions were screened. Our results indicated that 13-SPX-C was almost completely metabolized with both rat and human liver S9. Using a receptor binding assay towards nicotinic acetylcholine receptors we demonstrated that the resulting metabolites showed less affinity towards nicotinic acetylcholine receptors than 13-SPX-C. Finally, we showed that 13-SPX-C induced a pronounced increase of gene expression of the drug-metabolizing enzyme cytochrome P450 (CYP) CYP1A2. The role of this CYP in 13-SPX-C metabolism was clarified using an innovative in vitro tool, CYP1A2-Silensomes™. In summary, this study highlights that liver first-pass metabolism can contribute to the detoxification of 13-SPX-C.
13-去甲石房蛤毒素 C（13-SPX-C）是一种由甲藻产生的藻类毒素，可在贝类中积累。13-SPX-C 通过阻断烟碱型乙酰胆碱受体在啮齿动物中引起神经毒性作用。由于迄今为止尚未有人类因食用受 13-SPX-C 污染的海鲜而中毒，因此这种毒素不受《食品法典》监管。尽管如此，贝类消费者仍可能通过食用贝类而接触到 13-SPX-C。为了跟踪摄入后毒素的命运，并验证代谢解毒是否可以解释人类中毒的缺乏，我们使用几种体外肝脏系统评估了 13-SPX-C 的代谢。首先，筛选了大鼠和人肝 S9 级分中发生的 I 相和 II 相反应。我们的结果表明，13-SPX-C 几乎完全被大鼠和人肝 S9 代谢。使用针对烟碱型乙酰胆碱受体的受体结合测定法，我们证明了产生的代谢物对烟碱型乙酰胆碱受体的亲和力低于 13-SPX-C。最后，我们表明 13-SPX-C 诱导药物代谢酶细胞色素 P450（CYP）CYP1A2 的基因表达明显增加。使用创新的体外工具 CYP1A2-Silensomes™，阐明了该 CYP 在 13-SPX-C 代谢中的作用。总之，这项研究强调了肝脏首过代谢可以有助于 13-SPX-C 的解毒。
