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Histopathological examination of liver and lung as well as blood analysis of rats which wereorally treated with selected pyrrolizidine alkaloids over 28 days
Project
Project code: BfR-LMS-08-1329-554
Contract period: 01.04.2017
- 30.10.2017
Purpose of research: Experimental development
1,2-unsaturated pyrrolizidine alkaloids (PA) are a group of ubiquitously occuring phytochemicals. So far, over 500 PAs have been analyzed. Acute PA poisoning via food contamination causes severe damage to the liver such as venoocclusive disease. Chronic exposure or/and sub-lethal doses may cause cumulative damage which is characterized by hepatic necrosis, fibrosis and cirrhosis. 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 conversion of PA by enzymes predominantly expressed in the liver and among others is based on adduct formation of 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 fully elucidated. In vitro studies using primary human hepatocytes showed a structuredependent induction of gene expression pointing to a disturbance of liver function. Additionally we investigated a repeated dose exposure of human hepatoma cell line HepaRG using low concentrations of PA resulting in a decreased cell viability and a disturbance of bile salt excretion. However, there were no data/long time studies available dealing with a systematic structure-dependent analysis of molecular effect on target organs like liver and lung in the whole organism. To close this knowledge gap we commissioned a subacute 28 days study with rats, which are orally treated with different PA. This study shall contribute to a better understanding of PA’s mode of action in vivo resulting in a better, appropriate risk assessment.
Section overview
Subjects
- Toxicology
