{{Short description|Group of chemical compounds}} {{Use dmy dates|date=May 2024}} '''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.<ref name="chem">{{cite book |url=https://books.google.com/books?id=Fl4sdCYrq3cC&q=Grayanotoxin+asa+gray&pg=PA170 |title=Elsevier's Dictionary of Chemoetymology |last=Senning |first=Alexander |name-list-style=vanc |publisher=Elsevier |year=2007 |isbn=978-0-444-52239-9 |location=Amsterdam |page=170}}</ref> Grayanotoxin I (grayanotoxane-3,5,6,10,14,16-hexol 14-acetate) is also known as '''andromedotoxin''', '''acetylandromedol''', '''rhodotoxin''' and '''asebotoxin'''.<ref>{{cite book |title=The Merck Index |url=https://archive.org/details/merckindexencycl00wind |url-access=registration |publisher=Merck |year=1983 |edition=10th |location=Rahway, NJ |pages=[https://archive.org/details/merckindexencycl00wind/page/652 652–653] |isbn=9780911910278}}</ref> 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.<ref name="Jansen-2012">{{cite journal |vauthors=Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA |title=Grayanotoxin poisoning: 'mad honey disease' and beyond |journal=Cardiovascular Toxicology |volume=12 |issue=3 |pages=208–15 |date=September 2012 |pmid=22528814 |pmc=3404272 |doi=10.1007/s12012-012-9162-2}}</ref>
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.<ref name="Jansen-2012" /><ref>{{cite journal |vauthors=Demircan A, Keleş A, Bildik F, Aygencel G, Doğan NO, Gómez HF |title=Mad honey sex: therapeutic misadventures from an ancient biological weapon |journal=Annals of Emergency Medicine |volume=54 |issue=6 |pages=824–9 |date=December 2009 |pmid=19683834 |doi=10.1016/j.annemergmed.2009.06.010}}</ref> It is most frequently produced and consumed in regions of Turkey and Nepal as a recreational drug and traditional medicine.<ref name="gunduz">{{cite journal |vauthors=Gunduz A, Şimşek P, Ayaz FA |title=Worldwide distribution and clinical characteristics of mad honey poisoning cases |journal=Central European Journal of Public Health |volume=31 |issue=1 |pages=69–73 |date=March 2023 |pmid=37086424 |doi=10.21101/cejph.a7501 |url=https://cejph.szu.cz/pdfs/cjp/2023/01/11.pdf |access-date=15 February 2024 |archive-date=15 February 2024 |archive-url=https://web.archive.org/web/20240215202524/https://cejph.szu.cz/pdfs/cjp/2023/01/11.pdf |url-status=live }}</ref><ref name="Sahin-2015">{{Cite journal |last=Sahin |first=Huseyin |name-list-style=vanc |date=18 April 2015 |title=Grayanotoxin-III Detection and Antioxidant Activity of Mad Honey |journal=International Journal of Food Properties |volume=18 |issue=12 |pages=2665–2674 |doi=10.1080/10942912.2014.999866 |s2cid=97859238 |doi-access=free}}</ref>
== Origin == thumb|''Rhododendron luteum'' Grayanotoxins are produced by plants in the family Ericaceae, specifically members of the genera ''Agarista'', ''Craibiodendron'', ''Kalmia'', ''Leucothoe'', ''Lyonia'', ''Pieris'' and ''Rhododendron''.<ref name="Jansen-2012"/><ref name="EFSA CONTAM Panel-2023">{{cite journal |display-authors=3 |last1=Schrenk |first1=Dieter |last2=Bignami |first2=Margherita |last3=Bodin |first3=Laurent |last4=Chipman |first4=James Kevin |last5=del Mazo |first5=Jesús |last6=Grasl-Kraupp |first6=Bettina |last7=Hogstrand |first7=Christer |last8=Hoogenboom |first8=Laurentius (Ron) |last9=Leblanc |first9=Jean-Charles |last10=Nebbia |first10=Carlo Stefano |last11=Nielsen |first11=Elsa |last12=Ntzani |first12=Evangelia |last13=Petersen |first13=Annette |last14=Sand |first14=Salomon |last15=Schwerdtle |first15=Tanja |last16=Vleminckx |first16=Christiane |last17=Dusemund |first17=Birgit |last18=Hart |first18=Andrew |last19=Mulder |first19=Patrick |last20=Viviani |first20=Barbara |last21=Anastassiadou |first21=Maria |last22=Cascio |first22=Claudia |last23=Riolo |first23=Francesca |last24=Wallace |first24=Heather |title=Risks for human health related to the presence of grayanotoxins in certain honey |journal=EFSA Journal |date=March 2023 |volume=21 |issue=3 |pages=e07866 |doi=10.2903/j.efsa.2023.7866 |pmid=36875862 |url=https://www.efsa.europa.eu/en/efsajournal/pub/7866 |access-date=17 April 2024 |pmc=9978999 |archive-date=14 May 2024 |archive-url=https://web.archive.org/web/20240514074955/https://www.efsa.europa.eu/en/efsajournal/pub/7866 |url-status=live }}</ref> The genus ''Rhododendron'' alone encompasses over 750 species that grow around the world in parts of Europe, North America, Japan, India, Bhutan, Nepal and Turkey. They can grow at a variety of altitudes, ranging from sea level to more than {{convert|3|km|ft}}.<ref name="Sahin-2015"/> 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.<ref name="gunduz"/> thumb|''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.<ref name="Jansen-2012" />
==Chemical structure== left|248x248px {| class="wikitable" |- | '''Grayanotoxin''' | '''R<sup>1</sup>''' | '''R<sup>2</sup>''' | '''R<sup>3</sup>''' |- | Grayanotoxin I | OH | CH<sub>3</sub> | Ac |- | Grayanotoxin II | colspan="2" align="center" | CH<sub>2</sub> | H |- | Grayanotoxin III | OH | CH<sub>3</sub> | H |- | Grayanotoxin IV | colspan="2" align="center" | CH<sub>2</sub> | Ac |}
Grayanotoxins are low molecular weight hydrophobic compounds.<ref name="Sperelakis-2011">{{Cite book |title=Cell Physiology Source Book: Essentials of Membrane Biophysics |last=Sperelakis |first=Nicholas |name-list-style=vanc |publisher=Elsevier Science & Technology |year=2011 |isbn=9780123877383 |pages=510–513}}</ref> They are structurally characterized as polyhydroxylated cyclic diterpenes. The base structure is a 5/7/6/5 ring system that does not contain nitrogen.<ref name="Jansen-2012" /> More than 25 grayanotoxin isoforms have been identified from ''Rhododendron'' species<ref name="Sahin-2015" />'','' 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.<ref name="Jansen-2012" />
== Mechanism of action == thumb|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 Na''<sub>v</sub>''1.''x'' channels consist of four homologous domains (I-IV), each containing six transmembrane alpha-helical segments (S1-S6). Grayanotoxin has a binding affinity (IC<sub>50</sub>) of approximately 10 μM and binds the group II receptor site located on segment 6 of domains I and IV (IS6 and IVS6).<ref name="Jansen-2012" /> Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine.<ref name="Sperelakis-2011" />
Experiments using squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron.<ref>{{cite journal |vauthors=Seyama I, Yamada K, Kato R, Masutani T, Hamada M |title=Grayanotoxin opens Na channels from inside the squid axonal membrane |journal=Biophysical Journal |volume=53 |issue=2 |pages=271–4 |date=February 1988 |pmid=2449919 |pmc=1330147 |doi=10.1016/s0006-3495(88)83088-1 |bibcode=1988BpJ....53..271S}}</ref> 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 Na''<sub>v</sub>''1.''x'' agonist.<ref name="Sperelakis-2011" />
==Clinical effects == Although mad honey is used in traditional medicine in Turkey,<ref name="Jansen-2012" /><ref name=gunduz/> the majority of grayanotoxin poisoning cases occur in middle-aged males who use the honey for perceived sexual enhancement.<ref>{{cite journal |vauthors=Eroğlu SE, Urgan O, Onur OE, Denizbaşı A, Akoğlu H |title=Grayanotoxin (mad honey) – ongoing consumption after poisoning |journal=Balkan Medical Journal |volume=30 |issue=3 |pages=293–5 |date=September 2013 |pmid=25207122 |pmc=4115918 |doi=10.5152/balkanmedj.2013.8100}}</ref> Slowing of heart rate and lowering of blood pressure are typical effects reported in one review of cases.<ref name=gunduz/> Dizziness, nausea, fainting, and weakness were reported as common neurological outcomes.<ref name="Jansen-2012" /><ref name=gunduz/><ref name="Assimon-2012"/> 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.<ref name=gunduz/><ref>{{cite journal |vauthors=Sayin MR, Karabag T, Dogan SM, Akpinar I, Aydin M |title=Transient ST segment elevation and left bundle branch block caused by mad-honey poisoning |journal=Wiener Klinische Wochenschrift |volume=124 |issue=7–8 |pages=278–81 |date=April 2012 |pmid=22527815 |doi=10.1007/s00508-012-0152-y |s2cid=21598407}}</ref>
The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve).<ref name="Jansen-2012" /> 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 M<sub>2</sub>-subtype muscarinic acetylcholine receptors (mAChR).<ref>{{cite journal |vauthors=Onat FY, Yegen BC, Lawrence R, Oktay A, Oktay S |title=Mad honey poisoning in man and rat |journal=Reviews on Environmental Health |volume=9 |issue=1 |pages=3–9 |date=1991 |pmid=1957047 |doi=10.1515/reveh.1991.9.1.3 |bibcode=1991RvEH....9..1.3O |s2cid=12261007 |url=http://dergipark.gov.tr/marumj/issue/23668/252067 |hdl=11424/218274 |hdl-access=free |access-date=24 July 2019 |archive-date=17 October 2021 |archive-url=https://web.archive.org/web/20211017155954/http://dergipark.gov.tr/marumj/issue/23668/252067 |url-status=dead }}</ref> In severe cases of grayanotoxin poisoning, atropine {{ndash}} a non-specific "mAChR antagonist" or Muscarinic antagonist {{ndash}} can be used to treat bradycardia and other heart rhythm malfunctions.<ref name="Assimon-2012"/> In addition to correcting rhythm disorders, administration of fluids and vasopressors can also help treat hypotension and mitigate other symptoms.<ref name="Assimon-2012">{{Cite web |url=https://www.fda.gov/downloads/Food/FoodborneIllnessContaminants/UCM297627.pdf |title=Grayanotoxins. In: Bad Bug Book: Handbook of Foodborne Pathogenic Microorganisms and Natural Toxins |vauthors=Assimon SA |date=2012 |publisher=US Food and Drug Administration |access-date=3 May 2018 |archive-date=18 April 2013 |archive-url=https://web.archive.org/web/20130418013247/https://www.fda.gov/downloads/Food/FoodborneIllnessContaminants/UCM297627.pdf |url-status=dead }}</ref>
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.<ref name="Assimon-2012" />
==Animal poisoning== In contrast to humans, grayanotoxin poisoning can be lethal for other animals.<ref name="Jansen-2012" /> 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.<ref>{{cite journal |last1=Stephanie Pain |date=25 April 2015 |title=Bitter sweet nectar: Why some flowers poison bees |url=https://www.newscientist.com/article/mg22630180-500-bitter-sweet-nectar-why-some-flowers-poison-bees |journal=New Scientist |access-date=3 March 2018 |archive-date=4 March 2018 |archive-url=https://web.archive.org/web/20180304172416/https://www.newscientist.com/article/mg22630180-500-bitter-sweet-nectar-why-some-flowers-poison-bees/ |url-status=live }}</ref>
== Mad honey intoxication== {{main|Mad honey}} Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins.<ref name="Jansen-2012" /><ref name="Assimon-2012"/> 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.<ref name="Assimon-2012"/>
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%).<ref name=gunduz/> 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.<ref>{{cite news |url=https://www.theguardian.com/lifeandstyle/2014/oct/01/mad-honey-hot-honey-mead-buzz |title=The buzz about 'mad honey', hot honey and mead |first=Jamie |last=Waters |name-list-style=vanc |date=1 October 2014 |work=The Guardian}}</ref> In Nepal, this type of honey is used by the Gurung people for both its hallucinogenic properties and supposed medicinal benefits.<ref>{{cite web |url=http://topdocumentaryfilms.com/hallucinogen-honey-hunters/ |title=Hallucinogen honey hunters |last1=Treza |first1=Raphael |name-list-style=vanc |date=2011 |website=topdocumentaryfilms.com |access-date=20 October 2015 |archive-date=22 October 2015 |archive-url=https://web.archive.org/web/20151022200922/http://topdocumentaryfilms.com/hallucinogen-honey-hunters/ |url-status=live }}</ref>
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.<ref name="Assimon-2012"/><ref name="mad honey">{{cite journal |first=Adrienne |last=Mayor |name-list-style=vanc |title=Mad Honey! |url=https://www.academia.edu/966648 |journal=Archaeology |volume=46 |issue=6 |pages=32–40 |access-date=2 November 2017 |archive-date=1 May 2023 |archive-url=https://web.archive.org/web/20230501034722/https://www.academia.edu/966648 |url-status=live }}</ref><ref>{{cite book |url=https://books.google.com/books?id=4c5UAQAAQBAJ&pg=PA223 |title=Medicinal Plants in Australia Volume 1: Bush Pharmacy |first=Cheryll |last=Williams |name-list-style=vanc |publisher=Rosenberg Publishing |year=2010 |isbn=978-1877058790 |page=223}}</ref>
===Other grayanotoxin sources=== 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.<ref name="Assimon-2012"/><ref>{{cite book |url=https://books.google.com/books?id=p-ii-nVqFCIC&q=bee+intoxication&pg=RA1-PA80 |title=Bee Products: Properties, Applications, and Apitherapy |first=Yaacov |last=Lensky |name-list-style=vanc |publisher=Springer |year=1997 |isbn=0-306-45502-1 |access-date=17 October 2020 |archive-date=14 May 2024 |archive-url=https://web.archive.org/web/20240514100027/https://books.google.com/books?id=p-ii-nVqFCIC&q=bee+intoxication&pg=RA1-PA80 |url-status=live }}</ref> Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness.<ref name="Assimon-2012"/> 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.<ref name="Wittmann-1995">{{cite journal |vauthors=Wittmann D, Radtke R, Zeil J, Lübke G, Francke W |title=Robber bees (Lestrimelitta limao) and their host chemical and visual cues in nest defense byTrigona (Tetragonisca) angustula (Apidae: Meliponinae) |journal=Journal of Chemical Ecology |volume=16 |issue=2 |pages=631–41 |date=February 1990 |pmid=24263518 |doi=10.1007/bf01021793 |bibcode=1990JCEco..16..631W |s2cid=34424143}}</ref>
=== Historical use === The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder<ref name="mad honey" /><ref>{{cite book |title=Natural History |chapter=21.45—Maddening honey |chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.02.0137%3Abook%3D21%3Achapter%3D45 |author=Pliny the Elder |access-date=7 February 2021 |archive-date=29 January 2022 |archive-url=https://web.archive.org/web/20220129032520/http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.02.0137%3Abook%3D21%3Achapter%3D45 |url-status=live }}</ref> and Columella, all reporting illness from eating "maddening" honey believed to be from the pollen or nectar of ''Rhododendron luteum'' and ''Rhododendron ponticum''.<ref>{{cite journal |last=Kelhoffer |first=James A. |name-list-style=vanc |year=2005 |title=John the Baptist's "Wild Honey" and "Honey" in Antiquity |url=https://docs.google.com/viewer?a=v&pid=sites&srcid=c2x1LmVkdXxqYW1lcy1rZWxob2ZmZXJ8Z3g6MTY5MzJmMWJhZWMzMDk3NQ |journal=Greek, Roman, and Byzantine Studies |volume=45 |pages=59–73 |access-date=9 June 2017 |archive-date=10 October 2023 |archive-url=https://web.archive.org/web/20231010132054/https://docs.google.com/viewer?a=v&pid=sites&srcid=c2x1LmVkdXxqYW1lcy1rZWxob2ZmZXJ8Z3g6MTY5MzJmMWJhZWMzMDk3NQ |url-status=live }}</ref> 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.<ref>{{cite book |editor-first=Carleton L. |editor-last=Brownson |name-list-style=vanc |author=Xenophon |title=Anabasis |chapter=4.8.19–21 |chapter-url=https://www.perseus.tufts.edu/hopper/text?doc=Xen.%20Anab.%204.8&lang=original |publisher=Department of the Classics, Tufts University. |access-date=20 February 2021 |archive-date=13 August 2022 |archive-url=https://web.archive.org/web/20220813031613/https://www.perseus.tufts.edu/hopper/text?doc=Xen.%20Anab.%204.8&lang=original |url-status=live }}</ref>
== See also == *''Incilius alvarius'' *''Sarpa salpa'' *Potassium channel
== References == {{reflist|30em}} {{commons category|Grayanotoxins}}
Category:Beekeeping Category:Neurotoxins Category:Ion channel toxins Category:Diterpenes Category:Cyclopentanes Category:Sodium channel openers Category:Plant toxins Category:Non-protein ion channel toxins