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Identification of the structure-dependent toxicity of hepatotoxic pyrrolizidine alkaloids (PA1)

07/2016-08/2019

This third-party funded project is conducted in the framework of the BfR research programme on modern methods in toxicology.

DFG grant number: LA1177/12-1

Project homepage: http://gepris.dfg.de/gepris/projekt/315853093?language=en

Project description:

Unsaturated pyrrolizidine alkaloids (PA) belong to the most toxic compounds; more than 400 PA have been described in a wide range of plants. They are also found in Senecio vulgaris L. PA are toxic to humans and animals. PA were detected in substantial amounts in honey and tea. Acute PA poisoning via food contamination causes severe damage to the liver; long-term, sub-lethal doses may cause cumulative damage or cancer. Animal studies revealed that PA are carcinogenic. Mutagenicity of PA was observed in several in vitro and in vivo test systems. The toxicity of these compounds is associated with enzymatic reactions by enzymes dominantly expressed in the liver and dependent on PA´s bioavailability. However, the mode of action of PA to generate hepatotoxicity is not yet identified. Based on our results for bioavailability and the molecular mode of action of the structurally different PA echimidine, heliotrine, senecionine, and senkirkine, we hypothesise that PA act in a structure-dependent manner. We therefore aimed to group the PA structure- and toxicity-dependent within this project. For this purpose, bioavailability will be studied further in an in vitro model for the human intestinal barrier with a larger set of PA (22). ABCB1-dependent transport/detoxification will be investigated as the endpoint for grouping the structure-dependent mode of action of PA. The molecular mechanism of PA hepatic toxicity will also be analysed. Differences in the induction of gene expression in the liver were already shown  in our transcriptomic study with the 4 structurally different PA. Accordingly, in vivo analysis of the induction of hepatotoxicity in mice in real time is to  be analysed using two-photon excitation microscopy. The structure-dependent induction of toxicity is to be investigated using specific liver markers in wild type mice and in a further step, in Abcb1 knockout mice. The identified toxic effects on the liver will be correlated with the transcriptomics data from human primary hepatocytes. Based on these results, specific genes and signalling pathways are to be verified with regard to a structure-dependent induction of PA using quantitative real time PCR and reporter gene assays respectively.This study aimed to close gaps with regard to the structure-dependent PA bioavailability and hepatic mode of action to form a PA toxicity group on the basis of its different structure. These data should contribute to a better understanding of the toxic consequences of an acute or chronic PA uptake to enhance the protection of humans.

Project partners:

• TU Dortmund University, Germany
• Netherlands Cancer Institute, Netherlands

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