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Imprint
Molecular mode of action of a long-term exposure to hepatotoxisch pyrrolizidine alkaloids
Project
Project code: BfR-LMS-08-1322-624
Contract period: 01.01.2015
- 31.12.2016
Purpose of research: Basic research
1,2-unsaturated pyrrolizidine alkaloids (PA) are a group of phytochemicals, which occur ubiquitously in the plant kingdom and are count among the most toxic substances known. They occur in more than 6000 plant species, such as Senecio vulgaris L., where they contribute to the defense mechanism. So far, over 400 PA of different structure and the respective N-oxides could be analyzed. 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 among others is based on adduct formation of the reactive metabolites with DNA and proteins which in turn is dependent on the enzyme activity and oral bioavailability. However, the mode of action of PA to generate hepatotoxicity is not yet identified.
Initial studies concerning the molecular mode of action of a short-term exposure to PA (whole genome µ array), gained in the BfR research project “development of a hepatic in vitro test system for the sensitive detection of pyrrolizidine alkaloids” (1322-454), showed dramatically alteration of gene expression induced by the PA heliotrine, echimidine, senecionine and senkirkine. These effects were confirmed by qRT-PCR analysis to measure the effects of these PA on gene expression level in HepaRG cells, which were carried out within the BfR research project 'Structure-activity relationship of hepatotoxic pyrrolizidine alkaloids' (1322-591). These four PA represent all possible structural types of PA. They cover the three existing necic acid structure types (monoester, diester, cyclic diester) as well as the most frequent necic bases (retronecine, heliotridine, otonecine type).
The found strong regulatory effects of these four PA are attributed to a 24h short-term exposure. However, the exposure of humans to PA via food (especially tea or honey) is more likely to be continuous than singular, which in turn could lead to acute or chronic intoxications in the human organism (e.g. nausea, vomiting, ascites and hepatic veno-occlusive disease (VOD)). Thus, in the 2015 the molecular effects of a 14-day long-term exposure shall be investigated in HepaRG cells, initially with the four PA echimidine, heltiotrine, senecionine and senkirkine. Thereby the effects of long-term exposure to PA shall be compared to those of a short-term exposure (24 h) to identify similarities, differences or even possible new mechanisms. On the other hand, the effects of long-term exposure to PA on selected cellular characteristics (parameters: cytotoxicity, proliferation and apoptosis) shall be analysed in vitro. Furthermore, effects on the phosphoproteom shall be identified. These studies should help to elucidate the mode of action of the strong hepatotoxicity in humans.
Section overview
Subjects
- Toxicology
