Pyrrolizidine alkaloids

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Structural formula of pyrrolizidine (1-azabicyclo [3.3.0] octane)

Pyrrolizidine alkaloids (abbreviated PA) is a collective name for alkaloids whose basic structure contains the ring system pyrrolizidine , a bicyclic tertiary amine .

In nature, pyrrolizidine alkaloids occur worldwide as secondary plant substances in over 6000 different types of flowering plants, which mainly belong to the sunflower , predatory leaf , legume ( Crotalaria ) and orchid families . These substances serve the plants primarily to ward off browsing . To date, more than 660 different PA and PA amine oxides have been identified. About half of these compounds in the animal metabolism to reactive metabolites are converted, the hepatotoxic effect (hepatotoxic), for example, as it will make glutathione disrupt metabolism. Therefore, plants containing pyrrolizidine alkaloid can pose a potential hazard to livestock , wild animals and humans.

In addition, various insect species such as grasshoppers or butterflies ingest pyrrolizidine alkaloids ( pharmacophagy ), sequester them and use them as pheromones or as protection against predators.

Breakdown according to structure types

Bohemamin
Biosynthesis of retronecin

The pyrrolizidine alkaloids can be divided into higher-level groups, those of the necin type and those of the non-necin type. The term necin is derived from the plant genus Senecio (ragweed or ragweed), as it contains a particularly rich occurrence of alkaloids of this chemotype. Representatives of the Necine group are therefore also referred to as Senezioalkaloids .

The non-necines include, for example, Loline , Pyrrolame (the allocation of such amides to the alkaloids is dependent on the definition), Australine, Hyazynthazine, Bohemamine, Bistellettazine, Epohelmine, Jenamidine, Casuarine, Janfestin, Salinosporamid C, Heronamid A, Pochonizin, 1- epi - Alexin and Retronecanol.

Related alkaloid groups are based on indolizidine and quinolizidine bases, in which either only one ring or both rings are each one methylene group larger than the pyrrolizidine.

biosynthesis

The biosynthesis of retronecin takes place from putrescine (1) with the help of the key enzyme homospermidine synthetase (HSS) via the stages of homospermidine (2), the iminium ion (3a, 3b), trachelanthamidine (4) and finally to retronecin (7).

toxicology

Common groundwort ( Senecio vulgaris )

It is possible that pyrrolizidine alkaloids are introduced into the human food cycle via plant food components.

According to the Federal Institute for Risk Assessment (BfR) , impurities in teas and honey are the main sources of intake for pyrrolizidine alkaloids. Frozen and dried herbs can also be contaminated with 1,2-unsaturated pyrrolizidine alkaloids. Due to the toxicity of the pyrrolizidine alkaloids, the BfR advises against consuming such contaminated foods regularly or enjoying them in large quantities, but only calls for zero tolerance for the addition of toxic plant substances in isolated form.

The transfer of pyrrolizidine alkaloids into nectar and with this into honey has been proven. Studies have shown that German honeys are less contaminated. In 50% of the cases examined, however, the exposure was 250 µg / kg honey. This is even more critical with honeys from overseas.

Contamination of rocket and salad mixes with ragwort leaves and pyrrolizidine alkaloids in herbal teas has also been reported. To date, there are no regulations regarding maximum quantities or controls for food. However, for phytopharmaceutical products, the Federal Health Office limited the intake to 1 µg / day when used for up to six weeks or 0.1 µg / day when used over six weeks.

The risk is far greater in countries in the Near and Middle East and East Africa. In the 1970s, for example, there were three epidemic waves of liver disease in Uzbekistan , Pakistan and India with a total of around 6000 affected people and several deaths. The diseases were caused by the consumption of flour contaminated with solstice and crotalaria species , which had a high content of pyrrolizidine alkaloids. There have also been reports of child deaths from contaminated grain in Ethiopia and Afghanistan .

It is not the pyrrolizidine alkaloids themselves that have a toxic effect, but rather the degradation products of the compounds broken down in the liver , which are hepatotoxic and, in high doses, lead to fatal liver dysfunction, including hepatic venous obstruction . The clinical picture of PA poisoning is known in veterinary medicine as seniosis or "Schweinsberger disease" and is mostly caused by ragweed on pastures .

Toxicodynamics

On the path of poisoning , the alkaloids are enzymatically oxidized to hemiaminals , which are then converted into dehydropyrrolizidines through spontaneous dehydration . These compounds are unstable and react easily with nucleophiles by cleaving their respective carboxylic acid ester functions as nucleofuges . In this way, dehydropyrrolizidines form harmful adducts with cell proteins and with DNA in the organism . In an aqueous medium, the dehydropyrrolizidines have a half-life of 0.3 to 5 seconds.

ecology

The caterpillars of the Jacob wort bear ( Tyria jacobaeae ) feed on ragweed ( Senecio spec. ), Mainly Jacob's ragwort ( Senecio jacobaea ), to which they owe their name and on which they are not easy to spot due to their color . The poison is mainly bitter- tasting pyrrolizidine alkaloids, which are produced more intensively when neighboring plants are injured (grazing). These alkaloids are liver-toxic to vertebrates and serve to ward off herbivores. However, the pyrrolizidine alkaloids can also help locate the host plant, because they are scented by the specialized predator, the Jacob wort bear, in order to find the herb to lay eggs. Most of the pyrrolizidine alkaloids are not toxic to the Jacob wort bear. The caterpillars ingest it while eating and store it (sequestration), whereby they themselves become poisonous for other animals without being harmed themselves. Sometimes they also eat coltsfoot ( Tussilago farfara ) and butterbur ( Petasites spec. ).

proof

Chromatographic methods such as thin-layer chromatography , high-performance liquid chromatography or gas chromatography are suitable for detecting the pyrrolizidine alkaloids . For the detection by thin-layer chromatography, a conversion into the N- oxide and further derivatization is sometimes necessary. Due to the decomposition of the pyrrolizidine alkaloids, gas chromatographic determination requires a column temperature that is as moderate as possible or gentle heating. Reliable identification and separation of individual pyrrolizidine alkaloids is achieved by coupling HPLC with mass spectrometry .

literature

Web links

Commons : Pyrrolizidine Alkaloids  - Collection of Images, Videos, and Audio Files
Wiktionary: Alkaloids  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ Yan Xinmiao, Kang Hong, Feng Jun, Yang Yiyan, Tang Kailin, Zhu Ruixin, Yang Li, Wang Zhengtao, Cao Zhiwei: Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism. In: International Journal of Molecular Science. Volume 17, No. 3, March 2016, p. 318, doi: 10.3390 / ijms17030318 , PMC 4813181 (free full text)
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  4. ↑ Gadi VP Reddy, Angel Guerrero: Interactions of insect pheromones and plant semiochemicals. In: Trends in Plant Science. 9, 2004, pp. 253-261, doi: 10.1016 / j.tplants.2004.03.009 .
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  8. ↑ Suzan Fiack: Impurities in teas and honey are the main sources of intake for pyrrolizidine alkaloids. IDW, press release from September 29, 2016 at Informationsdienst Wissenschaft (idw-online.de), accessed on September 30, 2016.
  9. ↑ Federal Institute for Risk Assessment: Pyrrolizidine alkaloid content in dried and frozen spices and herbs too high. May 13, 2019, accessed July 10, 2019 .
  10. ↑ Zero tolerances in food and feed. (PDF; 205 kB). BfR position paper of March 12, 2007, p. 3.
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  15. ^ Federal Health Office (1992) Bundesanzeiger, 4805; German pharmacist newspaper. 132, pp. 1406-1408.
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  21. ↑ Mirka Macel, Klaas Vrieling: Pyrrolizidine alkaloids as oviposition stimulants for the cinnabar moth, Tyria jacobaeae. In: Journal of Chemical Ecology. 29, No. 6, 2003, pp. 1435-1446 researchgate.net (PDF).
  22. ↑ Mirka Macel, Peter G. Klinkhamer, Klaas Vrieling, Ed van der Meijden: Diversity of pyrrolizidine alkaloids in Senecio species does not affect the specialist herbivore Tyria jacobaeae. In: Oecologia. 133, No. 4, 2002, pp. 541-550 miekevd.home.xs4all.nl (PDF).
  23. ^ Dellbrücker Heide Retrieved June 11, 2012.
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