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，除了这些明显的急性效应外，冈田酸还表现出致癌和严重的细胞毒性以及胚胎毒性。中毒程度取决于与贝类一起摄入的冈田酸的量。我们的初步工作清楚地表明，需要区分低剂量和高剂量。我们认为，低剂量（低于50纳米）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。高剂量的中毒会破坏肠上皮的屏障功能，导致冈田酸被吸收进入血液系统并转运到肝脏。在这里，可以发生活性代谢产物的活化。本研究将利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，将使用不同的体内小鼠模型（敲除小鼠）来研究体内相关性。我们的调查将阐明在较低浓度范围内冈田酸对人类中毒的风险。此外，高剂量冈田酸中毒的未知毒性机制也有待确定。

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.