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]

Contents

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

Rhododendron luteum Rhododendron luteum2.jpg
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 Pontische rododendron struik (Rhododendron ponticum).jpg
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

Grayanotoxins.svg
GrayanotoxinR1R2R3
Grayanotoxin IOHCH3 Ac
Grayanotoxin IICH2H
Grayanotoxin IIIOHCH3H
Grayanotoxin IVCH2Ac

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

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

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

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

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

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

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

Related Research Articles

<span class="mw-page-title-main">Honey</span> Sweet and viscous substance made by bees mostly using nectar from flowers

Honey is a sweet and viscous substance made by several species of bees, the best-known of which are honey bees. Honey is made and stored to nourish bee colonies. Bees produce honey by gathering and then refining the sugary secretions of plants or the secretions of other insects, like the honeydew of aphids. This refinement takes place both within individual bees, through regurgitation and enzymatic activity, and during storage in the hive, through water evaporation that concentrates the honey's sugars until it is thick and viscous.

<i>Rhododendron</i> Genus of flowering plants in the heath family Ericaceae

Rhododendron is a very large genus of about 1,024 species of woody plants in the heath family (Ericaceae). They can be either evergreen or deciduous. Most species are native to eastern Asia and the Himalayan region, but smaller numbers occur elsewhere in Asia, and in North America, Europe and Australia.

<span class="mw-page-title-main">Aconitine</span> Toxic plant alkaloid

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<i>Jacobaea vulgaris</i> Flowering plant, daisy family Asteraceae

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<span class="mw-page-title-main">Azalea</span> Subgroup of rhododendron flowering shrubs

Azaleas are flowering shrubs in the genus Rhododendron, particularly the former sections Tsutsusi (evergreen) and Pentanthera (deciduous). Azaleas bloom in the spring, their flowers often lasting several weeks. Shade tolerant, they prefer living near or under trees. They are part of the family Ericaceae.

<span class="mw-page-title-main">Pollination</span> Biological process occurring in plants

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<span class="mw-page-title-main">Labrador tea</span> Tea made from three related plant species

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<span class="mw-page-title-main">Batrachotoxin</span> Chemical compound

Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. In certain frogs, this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.

<span class="mw-page-title-main">Caucasian honey bee</span> Subspecies of western honey bee

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<span class="mw-page-title-main">Nectar source</span> Flowering plant that produces nectar

A nectar source is a flowering plant that produces nectar as part of its reproductive strategy. These plants create nectar, which attract pollinating insects and sometimes other animals such as birds.

<span class="mw-page-title-main">Nectarivore</span> Animal in which nectar is a main source of nutrition in their diet

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<i>Kalmia polifolia</i> Species of shrub

Kalmia polifolia, previously known as Kalmia glauca and commonly called bog laurel, swamp laurel, or pale laurel, is a perennial evergreen shrub of cold acidic bogs, in the family Ericaceae. It is native to north-eastern North America, from Newfoundland to Hudson Bay southwards.

<i>Apis laboriosa</i> Species of insect

Apis laboriosa or Himalayan giant honey bee, is the world's largest honey bee; single adults can measure up to 3.0 cm (1.2 in) in length. Before 1980, Apis laboriosa was considered to be a subspecies of the widespread Apis dorsata, the giant honey bee, but in 1980 and for almost 20 years thereafter it was elevated to the rank of a separate species. It was classified once again as a subspecies of Apis dorsata by Michael S. Engel in 1999, but was confirmed as a full species in 2020 on the basis of co-occurrence with Apis dorsata at many sites with no sign of interbreeding. It is highly adapted to its highland habitat in behavior.

<i>Rhododendron ponticum</i> Species of flowering plant in the heath family Ericaceae

Rhododendron ponticum, called common rhododendron or pontic rhododendron, is a species of flowering plant in the Rhododendron genus of the heath family Ericaceae. It is native to the Iberian Peninsula in southwest Europe and the Caucasus region in northern West Asia.

<i>Rhododendron luteum</i> Species of plant

Rhododendron luteum, the yellow azalea or honeysuckle azalea, is a species of flowering plant in the heath family Ericaceae, native to southeastern Europe and southwest Asia. In Europe, it occurs from southern Poland and Austria, south through the Balkans, and east to southern Russia; and in Asia, east to the Caucasus.

<span class="mw-page-title-main">Mad honey</span> Psychoactive type of honey containing grayanotoxins

Mad honey is honey that contains grayanotoxins. The dark, reddish honey is produced from the nectar and pollen of genus Rhododendron and has intoxicating effects.

<span class="mw-page-title-main">Bees and toxic chemicals</span>

Bees can suffer serious effects from toxic chemicals in their environments. These include various synthetic chemicals, particularly insecticides, as well as a variety of naturally occurring chemicals from plants, such as ethanol resulting from the fermentation of organic materials. Bee intoxication can result from exposure to ethanol from fermented nectar, ripe fruits, and manmade and natural chemicals in the environment.

<i>Rhododendron periclymenoides</i> Species of shrub

Rhododendron periclymenoides, the pink azalea or pinxter flower, is a species of shrub in the heath family Ericaceae. It is native to eastern North America, where it is widespread from Alabama to New Hampshire. It is often found in riparian areas, in wet to dry forests.

<i>Lestrimelitta limao</i> Species of bee

Lestrimelitta limao is a neotropical eusocial bee species found in Brazil and Panama and is part of the Apidae family. It is a species of stingless bees that practices obligate nest robbing. They have never been spotted foraging from flowers, an observation that supports their raiding behavior. Because of their lack of hind corbiculae, they must raid to obtain enough protein in their diet in the form of pollen and nectar. Lestrimelitta limao secrete a lemon-scented alarm allomone, from which they receive their name, in order to conduct successful raids. L. limao are hypothesized to produce poisonous honey that is toxic if consumed by humans. Because robber bees are so rare and difficult to observe, there is a limited scope of information available.

<i>Lyonia mariana</i> Species of shrub

Lyonia mariana, the Piedmont staggerbush and staggerbush, is a perennial shrub that is native to the United States. Lyonia mariana, also known as the Piedmont staggerbush, is a shrub native to the southeastern United States, from Virginia to Florida. The shrub grows in habitats including pine flatwoods and sandhills, it displays adaptability to acidic soils. Recognized by its lance-shaped, glossy green leaves and clusters of white and pink tubular flowers, the Piedmont staggerbush contributes to the biodiversity of its ecosystem by providing shelter for wildlife and supporting pollinators. The plant contains grayanotoxins, making it potentially toxic if ingested.

References

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  2. ↑ The Merck Index (10th ed.). Rahway, NJ: Merck. 1983. pp.  652–653. ISBN   9780911910278.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 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.
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  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.
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