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引起腹泻性贝类中毒，主要导致肠道损伤。然而，除了这些典型的急性作用外，冈田酸还表现出致癌和严重的细胞毒性以及胚胎毒性特性。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。我们推测，低剂量(低于50 NM)通过外排机制在肠道上皮细胞中被主动解毒，从而保护身体免受全身摄取毒素的影响。高剂量的中毒会破坏肠道上皮的屏障功能，导致冈田酸进入血液系统并转运到肝脏。在这里，可以激活为反应性代谢物。解毒和生物活性之间的分子相互作用将在这项研究中使用体外测试系统来阐明。在该项目的后续阶段，将使用不同的体内-小鼠模型(基因敲除小鼠)来研究体内相关性。我们的调查将澄清冈田酸对人类的低浓度中毒的风险。此外，高剂量冈田酸中毒的未知毒性机制被认为是确定的。

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.