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Grayanotoxin

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Grayanotoxins are a group of closely related neurotoxins named after Leucothoe grayana, a plant native to Japan and named for 19th-century American botanist Asa Gray.[1] Grayanotoxin I (grayanotoxane-3,5,6,10,14,16-hexol 14-acetate) is also known as andromedotoxin, acetylandromedol, rhodotoxin and asebotoxin.[2] Grayanotoxins are produced by Rhododendron species and other plants in the family Ericaceae. Honey made from the nectar and so containing pollen of these plants also contains grayanotoxins and is commonly referred to as mad honey.[3]

Consumption of the plant or any of its secondary products, including mad honey, can cause a rare poisonous reaction called grayanotoxin poisoning, mad honey disease, honey intoxication, or rhododendron poisoning.[3][4] It is most frequently produced and consumed in regions of Turkey and Nepal as a recreational drug and traditional medicine.[5][6]

Origin

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Rhododendron luteum

Grayanotoxins are produced by plants in the family Ericaceae, specifically members of the genera Agarista, Craibiodendron, Kalmia, Leucothoe, Lyonia, Pieris and Rhododendron.[3][7] The genus Rhododendron alone encompasses over 750 species that grow around the world in parts of Europe, North America, Japan, Nepal and Turkey. They can grow at a variety of altitudes, ranging from sea level to more than 3 kilometres (9,800 ft).[6] While many of these species contain grayanotoxins, only a few contain significant levels. Species with high concentrations of grayanotoxins, such as R. ponticum and R. luteum, are most commonly found in regions of Turkey bordering the Black Sea, and in Nepal.[5]

Rhododendron ponticum

Nearly all parts of grayanotoxin-producing rhododendrons contain the molecule, including the stem, leaves, flower, pollen and nectar. Grayanotoxins can also be found in secondary plant products, such as honey, labrador tea, cigarettes, and herbal medicines.[3]

Chemical structure

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Grayanotoxin R1 R2 R3
Grayanotoxin I OH CH3 Ac
Grayanotoxin II CH2 H
Grayanotoxin III OH CH3 H
Grayanotoxin IV CH2 Ac

Grayanotoxins are low molecular weight hydrophobic compounds.[8] They are structurally characterized as polyhydroxylated cyclic diterpenes. The base structure is a 5/7/6/5 ring system that does not contain nitrogen.[3] More than 25 grayanotoxin isoforms have been identified from Rhododendron species[6], but grayanotoxin I and III are thought to be the principal toxic isoforms. Different Rhododendron species contain multiple different grayanotoxin isoforms, contributing to differences in plant toxicity.[3]

Mechanism of action

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Voltage-gated sodium channel with group II receptor site domains highlighted in red.

The toxicity of grayanotoxin is derived from its ability to interfere with voltage-gated sodium channels located in the cell membrane of neurons. The Nav1.x channels consist of four homologous domains (I-IV), each containing six transmembrane alpha-helical segments (S1-S6). Grayanotoxin has a binding affinity (IC50) of approximately 10 μM and binds the group II receptor site located on segment 6 of domains I and IV (IS6 and IVS6).[3] Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine.[8]

Experiments using squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron.[9] Additionally, grayanotoxin only binds to the activated conformation of sodium channels. Normally, voltage gated sodium channels are activated (opened) only when the cell membrane potential reaches a specific threshold voltage. This activated conformation allows for an influx of sodium ions resulting in cell depolarization, followed by the firing of an action potential. At the peak of the action potential, voltage-gated sodium channels are quickly inactivated and are only reset once the cell has repolarized to resting potential. When grayanotoxin is present, binding induces further conformational changes that prevent sodium channel inactivation and lead to a prolonged depolarization. Owing to its transient ability to activate channels and increase membrane permeability to sodium ions, grayanotoxin is classified as a reversible Nav1.x agonist.[8]

Clinical effects

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Although mad honey is used in traditional medicine in Turkey,[3][5] the majority of grayanotoxin poisoning cases occur in middle-aged males who use the honey for perceived sexual enhancement.[10] Slowing of heart rate and lowering of blood pressure are typical effects reported in one review of cases.[5] Dizziness, nausea, fainting, and weakness were reported as common neurological outcomes.[3][5][11] Other early-onset symptoms may include doubled and blurred vision, hypersalivation, perspiration, and paresthesia in the extremities and around the mouth. In higher doses, symptoms can include loss of coordination, severe and progressive muscular weakness, electrocardiographic changes of bundle branch block or ST-segment elevations as seen in ischemic myocardial threat, and nodal rhythm or Wolff-Parkinson-White syndrome.[5][12]

The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve).[3] The vagus nerve is a major component of the parasympathetic nervous system (a branch of the autonomic nervous system) and innervates various organs including the lungs, stomach, kidney and heart. Vagal stimulation of the heart is mediated by M2-subtype muscarinic acetylcholine receptors (mAChR).[13] In severe cases of grayanotoxin poisoning, atropine – a non-specific "mAChR antagonist" or Muscarinic antagonist – can be used to treat bradycardia and other heart rhythm malfunctions.[11] In addition to correcting rhythm disorders, administration of fluids and vasopressors can also help treat hypotension and mitigate other symptoms.[11]

Patients exposed to low doses of grayanotoxin typically recover within a few hours. In more severe cases, symptoms may persist for 24 hours or longer and may require medical treatment (as described above). Despite the risk from cardiac problems, grayanotoxin poisoning is rarely fatal in humans.[11]

Animal poisoning

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In contrast to humans, grayanotoxin poisoning can be lethal for other animals.[3] Nectar containing grayanotoxin can kill honeybees, though some seem to have resistance to it and can produce honey from the nectar (see below). According to a team of researchers from the UK and Ireland, worker bumblebees are not harmed and may be preferable as pollinators because they transfer more pollen. Consequently, it may be advantageous for plants to produce grayanotoxin to be pollinated by bumblebees.[14]

Mad honey intoxication

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Main article: Mad honey

Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins.[3][11] This so-called "mad honey" is the most common cause of grayanotoxin poisoning in humans. Small-scale producers of mad honey typically harvest honey from a small area or single hive to produce a final product containing a significant concentration of grayanotoxin. In contrast, large-scale honey production often mixes honey gathered from different locations, diluting the concentration of any contaminated honey.[11]

Mad honey is produced in specific world regions, notably the Black Sea region of Turkey (91% of poisoning cases in one analysis) and Nepal (5%).[5] In Turkey, mad honey known as deli bal is used as a recreational drug and traditional medicine. It is most commonly made from the nectar of Rhododendron luteum and Rhododendron ponticum in the Caucasus region.[15] In Nepal, this type of honey is used by the Gurung people for both its hallucinogenic properties and supposed medicinal benefits.[16]

In the 18th century, this honey was exported to Europe to add to alcoholic drinks to give them extra potency. In modern times, it is consumed locally and exported to North America, Europe and Asia.[11][17][18]

Other grayanotoxin sources

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In addition to various Rhododendron species, mad honey can also be made from several other grayanotoxin-containing plants. Honey produced from the nectar of Andromeda polifolia contains high enough levels of grayanotoxin to cause full body paralysis and potentially fatal breathing difficulties due to diaphragm paralysis.[11][19] Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness.[11] The honey from Lestrimelitta limao also produces a similar paralyzing effect to that of the honey from A. polifolia and is also toxic to humans.[20]

Historical use

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The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder[17][21] and Columella, all reporting illness from eating "maddening" honey believed to be from the pollen or nectar of Rhododendron luteum and Rhododendron ponticum.[22] According to Xenophon's Anabasis, an invading Greek army was accidentally poisoned by harvesting and eating the local Asia Minor honey, but they all made a quick recovery without any fatalities.[23] Having heard of this incident, and realizing that foreign invaders would be ignorant of the dangers of the local honey, King Mithridates later used the honey as a deliberate poison when Pompey's army attacked the Heptakometes in Asia Minor in 69 BC.[24] The Roman soldiers became delirious and nauseated after being tricked into eating the toxic honey, at which point Mithridates' army attacked.[25][26][27]

See also

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References

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  1. ^ Senning A (2007). Elsevier's Dictionary of Chemoetymology. Amsterdam: Elsevier. p. 170. ISBN 978-0-444-52239-9.
  2. ^ The Merck Index (10th ed.). Rahway, NJ: Merck. 1983. pp. 652–653. ISBN 9780911910278.
  3. ^ a b c d e f g h i j k l Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA (September 2012). "Grayanotoxin poisoning: 'mad honey disease' and beyond". Cardiovascular Toxicology. 12 (3): 208–15. doi:10.1007/s12012-012-9162-2. PMC 3404272. PMID 22528814.
  4. ^ Demircan A, Keleş A, Bildik F, Aygencel G, Doğan NO, Gómez HF (December 2009). "Mad honey sex: therapeutic misadventures from an ancient biological weapon". Annals of Emergency Medicine. 54 (6): 824–9. doi:10.1016/j.annemergmed.2009.06.010. PMID 19683834.
  5. ^ a b c d e f g Gunduz A, Şimşek P, Ayaz FA (March 2023). "Worldwide distribution and clinical characteristics of mad honey poisoning cases" (PDF). Central European Journal of Public Health. 31 (1): 69–73. doi:10.21101/cejph.a7501. PMID 37086424. Archived (PDF) from the original on 15 February 2024. Retrieved 15 February 2024.
  6. ^ a b c Sahin H (18 April 2015). "Grayanotoxin-III Detection and Antioxidant Activity of Mad Honey". International Journal of Food Properties. 18 (12): 2665–2674. doi:10.1080/10942912.2014.999866. S2CID 97859238.
  7. ^ Schrenk, Dieter; Bignami, Margherita; Bodin, Laurent; et al. (March 2023). "Risks for human health related to the presence of grayanotoxins in certain honey". EFSA Journal. 21 (3): e07866. doi:10.2903/j.efsa.2023.7866. PMC 9978999. PMID 36875862. Archived from the original on 14 May 2024. Retrieved 17 April 2024.
  8. ^ a b c Sperelakis N (2011). Cell Physiology Source Book: Essentials of Membrane Biophysics. Elsevier Science & Technology. pp. 510–513. ISBN 9780123877383.
  9. ^ Seyama I, Yamada K, Kato R, Masutani T, Hamada M (February 1988). "Grayanotoxin opens Na channels from inside the squid axonal membrane". Biophysical Journal. 53 (2): 271–4. Bibcode:1988BpJ....53..271S. doi:10.1016/s0006-3495(88)83088-1. PMC 1330147. PMID 2449919.
  10. ^ Eroğlu SE, Urgan O, Onur OE, Denizbaşı A, Akoğlu H (September 2013). "Grayanotoxin (mad honey) – ongoing consumption after poisoning". Balkan Medical Journal. 30 (3): 293–5. doi:10.5152/balkanmedj.2013.8100. PMC 4115918. PMID 25207122.
  11. ^ a b c d e f g h i Assimon SA (2012). "Grayanotoxins. In: Bad Bug Book: Handbook of Foodborne Pathogenic Microorganisms and Natural Toxins" (PDF). US Food and Drug Administration. Archived (PDF) from the original on 18 April 2013. Retrieved 3 May 2018.
  12. ^ Sayin MR, Karabag T, Dogan SM, Akpinar I, Aydin M (April 2012). "Transient ST segment elevation and left bundle branch block caused by mad-honey poisoning". Wiener Klinische Wochenschrift. 124 (7–8): 278–81. doi:10.1007/s00508-012-0152-y. PMID 22527815. S2CID 21598407.
  13. ^ Onat FY, Yegen BC, Lawrence R, Oktay A, Oktay S (1991). "Mad honey poisoning in man and rat". Reviews on Environmental Health. 9 (1): 3–9. doi:10.1515/reveh.1991.9.1.3. hdl:11424/218274. PMID 1957047. S2CID 12261007. Archived from the original on 17 October 2021. Retrieved 24 July 2019.
  14. ^ Stephanie Pain (25 April 2015). "Bitter sweet nectar: Why some flowers poison bees". New Scientist. Archived from the original on 4 March 2018. Retrieved 3 March 2018.
  15. ^ Waters J (1 October 2014). "The buzz about 'mad honey', hot honey and mead". The Guardian.
  16. ^ Treza R (2011). "Hallucinogen honey hunters". topdocumentaryfilms.com. Archived from the original on 22 October 2015. Retrieved 20 October 2015.
  17. ^ a b Mayor A. "Mad Honey!". Archaeology. 46 (6): 32–40. Archived from the original on 1 May 2023. Retrieved 2 November 2017.
  18. ^ Williams C (2010). Medicinal Plants in Australia Volume 1: Bush Pharmacy. Rosenberg Publishing. p. 223. ISBN 978-1877058790.
  19. ^ Lensky Y (1997). Bee Products: Properties, Applications, and Apitherapy. Springer. ISBN 0-306-45502-1. Archived from the original on 14 May 2024. Retrieved 17 October 2020.
  20. ^ Wittmann D, Radtke R, Zeil J, Lübke G, Francke W (February 1990). "Robber bees (Lestrimelitta limao) and their host chemical and visual cues in nest defense byTrigona (Tetragonisca) angustula (Apidae: Meliponinae)". Journal of Chemical Ecology. 16 (2): 631–41. Bibcode:1990JCEco..16..631W. doi:10.1007/bf01021793. PMID 24263518. S2CID 34424143.
  21. ^ Pliny the Elder. "21.45—Maddening honey". Natural History. Archived from the original on 29 January 2022. Retrieved 7 February 2021.
  22. ^ Kelhoffer JA (2005). "John the Baptist's "Wild Honey" and "Honey" in Antiquity". Greek, Roman, and Byzantine Studies. 45: 59–73. Archived from the original on 10 October 2023. Retrieved 9 June 2017.
  23. ^ Xenophon. "4.8.19–21". In Brownson CL (ed.). Anabasis. Department of the Classics, Tufts University. Archived from the original on 13 August 2022. Retrieved 20 February 2021.
  24. ^ Lane RW, Borzelleca JF (2007). "Harming and Helping Through Time: The History of Toxicology". In Hayes AW (ed.). Principles and methods of toxicology (5th ed.). Boca Raton: Taylor & Francis. ISBN 978-0-8493-3778-9. Archived from the original on 14 May 2024. Retrieved 17 October 2020.
  25. ^ Strabo. "12.3.18". Geography. Archived from the original on 14 May 2024. Retrieved 13 November 2017.
  26. ^ Georghiou GP (1980). "Ancient Beekeeping". In Root, A.I. (ed.). The ABC and XYZ of Bee Culture. Medina, Ohio: A.I. Root Company. pp. 17–21.
  27. ^ Ambrose JT (1972). Bees and Warfare: Gleanings in Bee Culture. pp. 343–6.
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