Investigation of the hepatoxic and genotoxic potency and the metabolization of food-relevant pyrrolizidine alkaloids

茶和草药冲剂以及其他植物源性食品中PA含量高的发现必须被视为食品安全的相关话题，特别是因为其中一些毒素被归类为遗传毒性致癌物。在不同类型的茶和草药冲剂中检测到的PA属于不同的结构类型，如茴香冲剂中主要发现开链PA酯，而红茶中以环状PA酯为主。更准确地说，食品中PA的含量是大量单独PA的总和，这些PA同时存在。由于没有关于PAs相对毒性的实质性数据，因此通常考虑单个PAs的总量进行风险评估。值得怀疑的是，这个程序是否足够，是否表明需要更好地了解PA的相对毒性。随着茶叶和草药冲泡植物的广泛生产的增加以及除草剂使用的预期减少，PAs等天然毒素可能成为一个日益严重的问题。过去，对有限数量的PAs进行了几项实验室动物毒性研究。监测的终点是急性毒性作用，如致死性或器官形态学改变。虽然存在结构依赖性毒性的提示，但由于测试的pa数量有限，并且由于研究设计限制了数据的可比性和相对效力的计算，因此无法得出关于单个pa的相对毒性的结论。该项目的目标是应用具有不同毒理学终点的体外测试系统，从而能够定量分析PAs的毒性作用。同时，商业上有更多的PA标准，涵盖了广泛的不同结构类型。因此，将同时测试这些物质对细菌和哺乳动物细胞的遗传毒性以及对肝细胞的细胞毒性。这些数据将用于评估PA的相对毒性。由于PAs是前毒素，而毒性仅在其代谢激活后才产生，因此代谢与毒性之间必然存在很强的关系。因此，已知产物的定量和未知代谢物的鉴定是合理解释毒性差异的重要一步。体外试验与代谢数据的相关性将被用作更好地了解PA毒性的工具，这是评估相对PA毒性的关键。

The findings of high PA amounts in tea and herbal infusions and other plant derived food have to be considered as a relevant topic in food safety, especially, as some of these toxins are classified as genotoxic carcinogens. The PAs detected in different types of tea and herbal infusions belonged to different structural types as for instance open chained PA esters are mainly found in fennel infusions, while black tea was dominated by cyclic PA esters. More precisely, PA amounts determined in food are the sum of a large number of individual PAs that occur in parallel. As no substantial data on the relative toxicities of PAs are available usually the sum-amounts of individual PAs were considered for risk assessment. It is questionable if this procedure is adequate and demonstrates the need for a better knowledge concerning relative PA toxicities. With an increase in the extensive production of plants for tea and herbal infusions and the intended reduction in herbicide use, natural toxins such as PAs are likely to become an increasing problem.In the past, several toxicity studies with laboratory animals were conducted for a limited number of PAs. Monitored endpoints were the acute toxic effects such as lethality or morphological changes in organs. Although hints for a structure dependent toxicity exist, no conclusions on the relative toxicities of individual PAs can be drawn due to the limited number of tested PAs and due to study designs that limited the comparability of data and the calculation of relative potencies.It is the goal of this project to apply in vitro test systems with different toxicological endpoints that enable the quantitative analysis of toxic effects of PAs. Meanwhile a higher number of PA standards are commercially available which cover a broad range of different structural types. Therefore, these will be tested in parallel for genotoxicity in bacteria and mammalian cells and for cytotoxicity in liver cells. The data will be used for assessing relative PA toxicities. As PAs are pro-toxins and toxicity is caused after their metabolic activation only, there has to be a strong relationship between metabolism and toxicity.. Therefore, the quantification of known products and identification of unknown metabolites is an important step towards a rational approach explaining differences in toxicity. The correlation of in vitro tests and metabolism data will be used as tool for a better understanding of PA toxicity, a key to risk assessment of relative PA toxicities.