Investigation of the hepatoxic and genotoxic potency and the metabolization of food-relevant pyrrolizidine alkaloids
Analytical Chemistry
Food Chemistry
Final Report Abstract
Pyrrolizidine alkaloids (PAs)are secondary plant metabolites famed by certain flowering plants in high structural diversity. They are metabolized in the I ive r to highly reactive metabolites, which can lead to acKerse health effects in humans and animals. Due to the co-harvesting of PA containing weeds, food of plant origin, such as herbal teas and spices, may show contamination with PM. It is likely that natural toxins such as PAs will become a challenge to crop food production due to climate change and the increase in extensive agriculture while reducing herbicide use. Combined with the desire and need to balance biodiversity and agricultural land use, it is likely that reliable data on the toxicity of individual PAs will be required for risk assessment. The aim of this project was to identify hepatically formed metabolites (in vitro incubation with liver microsomes) from humans and rats so that this process can be described as quantitatively as possible. In this project, for the first time, comprehensive analyses were performed to determine structural influences on the metabolism of PAs using 25 congeners with certified concentrations under standardized measurement conditions. From the set of 25 PAs, metabolite screening was performed for six representative PAs. The identified metabolites were classified into reactive or other metabolites based on their structures and toxic mechanisms of action reported in the literature. In this work, numerous such reactive, so-called pyrrolic metabolites, could be identified and structurally described in more detail. It was shown that the formation potential for reactive metabolites varies between the individual PAs and correlates with the observed toxic effect. The structural features that correlated with a high formation potential in the studies in this project can be summarized as follows: • Open-chain arid cyclic diesters of the heliotridine and retronecinol type substituted at the C7 position with angelic acid (including epoxide) exhibited high formation potential. For example, PAs such as lasiocarpine, echimedine, senecionine, retrorsine, riddelliine, jacobine belong to this group. Accordingly, low formation potential showed PAs that do not have this structure: • PAs that are not 1,2 unsaturated, such as platyphylline. • monoesters, such as lycopsamine, intermedin • open-chain diesters substituted at C7 with short-chain necine acids, such as acetic acid, e.g acetyllycopsamine • cyclic diesters that lack the angelic acid motif, such as jacolin. The data generated in this research project suggest that PAs with a lower formation potential also have a lower toxic effect potential. Investigating this hint in more detail would be relevant, for example, in light of the following: In nature, plants occur that almost exclusively form monoesters or occur in association with open-chain diesters substituted at C7 with short-chain necic adds, such as acetic add. Here, native plants such as Eupatorium or Borago may be mentioned as representatives. Against the above background, the toxic potential of such PA plants would have to be reconsidered, both from the point of view of consumer health protection and the protection of biodiversity.
Publications
- In vitro biotransformation of pyrrolizidine alkaloids in different species: part II-identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids. Archives of Toxicology, Vol. 94. 2020, pp. 3759–3774.
Geburek, I., D. Schrenk and A. These
(See online at https://doi.org/10.1007/s00204-020-02853-9) - In vitro metabolism of pyrrolizidine alkaloids - Metabolic degradation and GSH conjugate formation of different structure types. Food and Chemical Toxicology, Vol. 135. 2020, 110868.
Geburek, I., A. Preiss-Weigert, M. Lahrssen-Wiederholt, D. Schrenk and A. These
(See online at https://doi.org/10.1016/j.fct.2019.110868) - Metabolic Pattern of Hepatotoxic Pyrrolizidine Alkaloids in Liver Cells.
Chemical Research in Toxicology, Vol. 34. 2021, Issue 4, pp. 1101–1113.
Geburek, I., L. Rutz, L. Gao, J. H. Kupper, A. These and D. Schrenk
(See online at https://doi.org/10.1021/acs.chemrestox.0c00507)
