Grayanotoxins are a group of closely related named after Leucothoe grayana, a plant native to Japan and named for 19th-century American botanist Asa Gray.
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.
Origin
Grayanotoxins are produced by plants in the family
Ericaceae, specifically members of the
genera Agarista,
Craibiodendron,
Kalmia,
Leucothoe,
Lyonia,
Pieris and
Rhododendron.
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 .
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.
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.
Chemical structure
|
| Grayanotoxin | R1 | R2 | R3 |
| Grayanotoxin I | OH | CH3 | Acetyl |
| Grayanotoxin II | CH2 | H |
| Grayanotoxin III | OH | CH3 | H |
| Grayanotoxin IV | CH2 | Ac |
Grayanotoxins are low molecular weight Hydrophobe compounds.
Mechanism of action
The toxicity of grayanotoxin is derived from its ability to interfere with voltage-gated sodium channels located in the
cell membrane of
. The Na
v1.
x channels consist of four homologous
Protein domain (I-IV), each containing six transmembrane
Alpha helix segments (S1-S6). Grayanotoxin has a
binding affinity (IC
50) of approximately 10 μM and binds the group II receptor site located on segment 6 of domains I and IV (IS6 and IVS6).
Other toxins that bind to this region include the alkaloids
veratridine,
batrachotoxin and
aconitine.
Experiments using squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron.
Clinical effects
Although mad honey is used in traditional medicine in Turkey,
[ the majority of grayanotoxin poisoning cases occur in middle-aged males who use the honey for perceived sexual enhancement.][ Dizziness, nausea, fainting, and weakness were reported as common Neurology outcomes.]
The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve).
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.
Animal poisoning
In contrast to humans, grayanotoxin poisoning can be lethal for other animals.
Mad honey intoxication
Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins.
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%).[ 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.]
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.
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.
Historical use
The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder
See also
