Grayanotoxins

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Leucothoe grayana , a grape heather from which grayanotoxin was first extracted.

Grayanotoxins are a group of neurotoxic tetracyclophytans produced by various plants . Some of them are used as stimulants , but they also cause accidental poisoning. Grayanotoxins occur in both Labrador tea and Pontic honey .

Occurrence and history

Grayanotoxins.svg
Grayanotoxin R 1 R 2 R 3
Grayanotoxin I. OH CH 3 Ac
Grayanotoxin II CH 2 H
Grayanotoxin III OH CH 3 H
Grayanotoxin IV CH 2 Ac

Ac = acetyl

The Pontic Rhododendron ( Rhododendron ponticum ), namesake of the Pontic honey containing grayanotoxin.
Kalmia angustifolia , a bay rose , also contains grayanotoxin.

The first known representative of the grayanotoxins is grayanotoxin I. It is also known as andromedotoxin or rhodotoxin and was described in 1934 as the active component in an extract from Leucothoe grayana , a plant belonging to the grape heather genus . Grayanotoxins are found in numerous members of the heather family , as well as in the narrow-leaved bay rose Kalmia angustifolia or rosemary heather . They activate sodium ion channels and are therefore neurotoxic. Currently (as of 2016) more than 60 chemical compounds are known which, due to their chemical structure, are classified as grayanotoxins.

Extraction

Grayanotoxins can be extracted from plant material and purified using methods customary for plant diterpenes . Grayanotoxins are readily soluble in hot water, acetic acid , ethanol and methanol . Extraction with hot methanol and purification by chromatography are customary . Alternatively, the methanolic extract can be evaporated and the residue washed out with chloroform . After evaporation of the chloroform, an oily residue remains, from which grayanotoxin can be crystallized with ethyl acetate .

Biosynthesis and chemical synthesis

The biosynthesis of grayanotoxins is not fully understood, but experiments with radioactive markers have shown a synthetic route via mevalonic acid .

The total synthesis is challenging due to the unusual tetracyclic structure and the dense arrangement of hydroxy groups and requires numerous steps. However, total synthesis is interesting because of the potential pharmacological relevance of this class of compounds.

Symptoms of intoxication

Grayanotoxin poisoning is rarely fatal. The usual symptoms are profuse salivation, sweating, nausea, dizziness, weakness, and low blood pressure. Treatment of symptoms with atropine is rarely necessary. Poisoning symptoms caused by the consumption of plants containing grayanotoxin are also known in animals.

use

Especially Pontic honey , which comes from the nectar of the grayanotoxin-containing plant Rhododendron ponticum , is the cause of numerous poisonings. Grayanotoxins are said to have the effect of an aphrodisiac and so poisoning occurs when Pontic honey is consciously consumed as a luxury food. In addition, the Gurung , a people in Nepal , use honey containing grayanotoxin for its hallucinogenic properties. Because of its intoxicating effects, Pontic honey was added to various drinks in Europe in the 18th century.

Labrador Tea , a herbal tea that is enjoyed by Athabascans and Eskimos , is made from the leaves of the swamp porst and the Greenland porst , among other things . It contains grayanotoxin and in large quantities can trigger the typical symptoms of poisoning.

Grayanotoxin as a weapon

The Greek author and general Xenophon took part in a campaign of mainly Greek mercenaries of the Persian prince Cyrus against his brother Artaxerxes II , as he reports in the Anabasis . After Cyrus at the Battle of Kunaxa in 401 BC. BC fell, the Greek mercenaries and Xenophon withdrew and consumed honey on the way back in the area around Trapezus , which led to the typical symptoms. Since such honey can only be found in summer, the flowering time of the azaleas could be used to more accurately date the event.

Intentional poisoning with grayanotoxin and a subsequent military defeat caused about 1500 Roman soldiers under Gnaeus Pompeius Magnus around the year 67 BC. During the Mithridatic Wars . Grayanotoxin is therefore also referred to as the "ancient biological weapon". Reports from the time come from Strabon , who writes:

"The Heptacometae smote three maniples of Pompey army as they marched through the mountainous country; for they prepared bowls of the crazy honey that came from the branches of the trees, put the bowls by the road, and when the soldiers ingested it and lost their senses, they attacked and destroyed it. "

- Strabo : Geographika 12,3,18

In addition, Pliny the Elder and his contemporary Lucius Junius Moderatus Columella also report on the effects of such honey.

Individual evidence

  1. ^ A b S. Miyajima, S. Takei: The active constituents of Leucothoe grayana Max. In: Journal of the Agricultural Chemical Society of Japan. Volume 10, 1934, pp. 1093-1103.
  2. ↑ a b David G. Spoerke Jr., Susan C. Smolinske: Toxicity of Houseplants. CRC Press, Boca Raton / Ann Arbor / Boston 1990, ISBN 978-0-8493-6655-0 , pp. 25-28 ( online ).
  3. ^ S. Ito, Y. Nakazato, A. Ohga: Further evidence for the involvement of Na + channels in the release of adrenal catecholamine: the effect of scorpion venom and grayanotoxin I. In: British journal of pharmacology. Volume 72, Number 1, January 1981, pp. 61-67, PMID 6261866 , PMC 2071538 (free full text).
  4. ↑ a b T. Terai, K. Osakabe, M. Katai, K. Sakaguchi, I. Narama, T. Matsuura, J. Katakawa, T. Tetsumi: Preparation of 9-hydroxy grayanotoxin derivatives and their acute toxicity in mice. In: Chemical & pharmaceutical bulletin. Volume 51, Number 3, March 2003, pp. 351-353, PMID 12612430 .
  5. ↑ a b Tetsuya Masutani, Masayuki Hamada, Eiko Kawano, Junkichi Iwasa, Zenzaburo Kumazawa, Hiroo Ueda: Biosynthesis of Grayanotoxins in Leucothoe grayana Max, Incorporation of Mevalonic Acid and (-) - Kaurene into Grayanotoxin-III. In: Agricultural and Biological Chemistry. Volume 45, number 5, 1981, pp. 1281-1282, doi : 10.1080 / 00021369.1981.10864694 ( PDF; 142 KB ).
  6. ↑ T. Kan, S. Hosokawa, S. Nara, M. Oikawa, S. Ito, F. Matsuda, H. Shirahama: Total Synthesis of (-) - Grayanotoxin III. In: The Journal of Organic Chemistry. Volume 59, Number 19, 1994, pp. 5532-5534, doi : 10.1021 / jo00098a009 .
  7. ↑ a b A. Demircan, A. Keleş, F. Bildik, G. Aygencel, NO Doğan, HF Gómez: Mad honey sex: therapeutic misadventures from an ancient biological weapon. In: Annals of emergency medicine. Volume 54, number 6, December 2009, pp. 824-829, doi : 10.1016 / j.annemergmed.2009.06.010 , PMID 19683834 .
  8. ^ PM Scott, BB Coldwell, GS Wiberg: Grayanotoxins. Occurrence and analysis in honey and a comparison of toxicities in mice. In: Food and cosmetics toxicology. Volume 9, Number 2, April 1971, pp. 179-184, PMID 5559997 .
  9. ↑ B. Puschner, DM Holstege, N. Lamberski: Grayanotoxin poisoning in three goats. In: Journal of the American Veterinary Medical Association. Volume 218, Number 4, February 2001, pp. 573-575, 527, PMID 11229512 .
  10. ↑ M. Yarlioglues, M. Akpek, I. Ardic, D. Elcik, O. Sahin, MG Kaya: Mad-honey sexual activity and acute inferior myocardial infarctions in a married couple. In: Texas Heart Institute journal. Volume 38, Number 5, 2011, pp. 577-580, PMID 22163140 , PMC 3231547 (free full text).
  11. ^ SA Jansen, I. Kleerekooper, ZL Hofman, IF Kappen, A. Stary-Weinzinger, MA van der Heyden: Grayanotoxin poisoning: 'mad honey disease' and beyond. In: Cardiovascular toxicology. Volume 12, number 3, September 2012, pp. 208-215, doi : 10.1007 / s12012-012-9162-2 , PMID 22528814 , PMC 3404272 (free full text) (review).
  12. ↑ Hallucinogen honey hunters 2011.
  13. ↑ a b Cheryll Williams: Medicinal Plants in Australia. Volume 1: Bush Pharmacy. Rosenberg Publishing, Dural 2010, ISBN 978-1-925078-05-3 , p. 223- ( online ).
  14. ↑ A. Dampc, M. Luczkiewicz: Labrador tea - the aromatic beverage and spice: a review of origin, processing and safety. In: Journal of the science of food and agriculture. Volume 95, Number 8, June 2015, pp. 1577-1583, doi : 10.1002 / jsfa.6889 , PMID 25156477 (review).
  15. ^ Adrienne Mayor: Mad Honey. In: Archeology. Volume 46, Number 6, pp. 32-40 ( online ).
  16. ↑ a b c James A. Kelhoffer: The Diet of John the Baptist: "Locusts and Wild Honey" in Synoptic and Patristic Interpretation (= Scientific Studies on the New Testament. Volume 176). Mohr Siebeck, Tübingen 2005, ISBN 978-3-16-148460-5 , pp. 88-92 ( online ).
  17. ↑ Shane Brennan: Mind the gap: A "snow lacuna" in Xenophon's Anabasis? In: Fiona Hobden, Christopher Tuplin (Eds.): Xenophon: Ethical Principles and Historical Inquiry. Brill, Leiden 2012, ISBN 90-04-22437-8 , p. 330– ( online ).