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

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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.