Grayanotoxin

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==

Grayanotoxins are low molecular weight hydrophobic compounds. They are structurally characterized as polyhydroxylated cyclic diterpenes. The base structure is a 5/7/6/5 ring system that does not contain nitrogen. More than 25 grayanotoxin isoforms have been identified from Rhododendron species, 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. == 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 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). 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. ==Clinical effects ==

Although mad honey is used in traditional medicine in Turkey, Slowing of heart rate and lowering of blood pressure are typical effects reported in one review of cases. The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve). 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. 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. In Nepal, this type of honey is used by the Gurung people for both its hallucinogenic properties and supposed medicinal benefits. 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. Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness. Historical use The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder and Columella, all reporting illness from eating "maddening" honey believed to be from the pollen or nectar of Rhododendron luteum and Rhododendron ponticum. 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. 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. The Roman soldiers became delirious and nauseated after being tricked into eating the toxic honey, at which point Mithridates' army attacked. == See also ==