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Molecular characterization of toxicological properties of the marine biotoxin okadaic acid in in vitro models for the human intestinal barrier and liver

海洋生物毒素冈田酸在人肠屏障和肝脏体外模型中毒理学特性的分子表征

基本信息

批准号：
252591399
负责人：
Professor Dr. Alfonso Lampen
金额：
--
依托单位：
Abteilung 5: Lebensmittelsicherheit
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/252591399?language=en
关键词：
Molecular characterization toxicological properties marine

项目摘要

The marine biotoxin okadaic acid causes diarrhetic shellfish poisoning primarily leading to enteral injury. However, besides these well characterised acute effects, okadaic acid exhibits carcinogenic and severe cytotoxic as well as embryotoxic properties. The extent of poisoning depends on the amount of okadaic acid ingested with shellfish. Our preliminary work clearly indicates the need to differentiate between low and high doses. We suppose that low doses (lower than 50 nM) are actively detoxified in the intestinal epithelium by an efflux mechanism resulting in protection of the body against the systemic uptake of the toxin. Intoxication with higher doses leads to the destruction of the barrier function of the intestinal epithelium resulting in the uptake of okadaic acid into the blood system and transport to the liver. Here, activation into reactive metabolites can occur. The molecular interactions between the detoxification and the bioactivation shall be elucidated in this study using in vitro test systems. In subsequent stages of this project the in vivo relevance shall be investigated using different in vivo-mouse models (knockout-mice). Our investigations shall clarify the risk of an okadaic acid poisoning in the lower concentration range for humans. Additionally, unknown toxicity mechanisms of a high doses intoxication of okadaic acid are supposed to be identified.

海洋生物毒素冈田酸可引起贝类中毒，主要导致肠道损伤。然而，除了这些充分表征的急性作用外，冈田酸还表现出致癌性和严重的细胞毒性以及胚胎毒性。中毒的程度取决于贝类摄入的冈田酸的量。我们的初步工作清楚地表明，需要区分低剂量和高剂量。我们假设低剂量（低于50 nM）在肠上皮中通过外排机制主动解毒，从而保护身体免受毒素的全身吸收。较高剂量的中毒导致肠上皮屏障功能的破坏，导致冈田酸被吸收到血液系统中并转运到肝脏。在这里，可以发生活化成反应性代谢物。本研究应使用体外试验系统阐明解毒和生物活化之间的分子相互作用。在本项目的后续阶段，应使用不同的体内小鼠模型（基因敲除小鼠）研究体内相关性。我们的研究将阐明在较低浓度范围内人类的冈田酸中毒风险。此外，尚不清楚冈田酸高剂量中毒的毒性机制。