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

食品相关吡咯里西啶生物碱的肝毒性和遗传毒性效力及代谢研究

• 批准号: 322267165
• 负责人: Professor Dr. Dieter Schrenk
• 金额: --
• 依托单位: Bundesinstitut für Risikobewertung (BfR)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/322267165?language=en
• 关键词: Investigation; hepatoxic; genotoxic; potency; metabolization

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.

茶和草药输液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主题，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浸泡液中检测到的PA属于不同的结构类型，例如开链PA酯主要存在于茴香浸泡液中，而红茶主要是环状PA酯。更确切地说，食物中测定的PA量是大量平行出现的单个PA的总和。由于没有关于PA相对毒性的实质性数据，通常考虑单个PA的总量进行风险评估。这是值得怀疑的，如果这个程序是足够的，并证明需要更好地了解相对PA毒性。随着茶叶和草药浸泡用植物的广泛生产的增加以及除草剂使用的预期减少，天然毒素（如PA）可能会成为一个日益严重的问题。过去，对有限数量的PA进行了几项实验室动物毒性研究。预期终点为急性毒性效应，如致死性或器官形态学变化。尽管存在结构依赖性毒性的提示，但由于受试PA数量有限，以及研究设计限制了数据的可比性和相对效价的计算，因此无法得出单个PA相对毒性的结论。本项目的目标是应用具有不同毒理学终点的体外试验系统，从而能够定量分析PA的毒性作用。与此同时，市场上有更多的PA标准，涵盖了广泛的不同结构类型。因此，将平行检测细菌和哺乳动物细胞的遗传毒性以及肝细胞的细胞毒性。数据将用于评估相对PA毒性。由于PA是前毒素，并且毒性仅在其代谢活化后引起，因此代谢和毒性之间必须有很强的关系。因此，已知产物的定量和未知代谢物的鉴定是解释毒性差异的合理方法的重要一步。体外试验和代谢数据的相关性将被用作更好地理解PA毒性的工具，这是相对PA毒性风险评估的关键。