Grayanotoxin

Grayanotoxins are a group of closely related neurotoxins named after Leucothoe grayana, a plant native to Japan originally named for 19th century American botanist Asa Gray. Grayanotoxin I (grayanotaxane-3,5,6,10,14,16-hexol 14-acetate) is also known as andromedotoxin, acetylandromedol, rhodotoxin and asebotoxin. Grayanotoxins are produced by Rhododendron species and other plants in the Ericaceae family. Honey made from the nectar and so containing pollen of these plants also contains grayanotoxins and is commonly referred to as mad honey. 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. It is most frequently produced and consumed in regions of Nepal and Turkey as a recreational drug and traditional medicine.Grayanotoxins are produced by plants in the Ericaceae family, specifically members of the Rhododendron, Pieris, Agarista and Kalmia genera. 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 three kilometers above. While many of these species contain grayanotoxins, only a few contain significant levels. Species with high concentrations of grayanotoxins such as R. ponticum, R. flavum and R. luteum are most commonly found in Nepal and regions of Turkey bordering the Black Sea.Ac = acetylThe 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). Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine.Prolonged sodium channel activation and cell depolarization leads to overstimulation of the central nervous system. Physical symptoms from grayanotoxin poisoning appear after a dose-dependent latent period of several minutes to approximately three hours. The most common clinical symptoms include various cardiovascular effects, nausea and vomiting, and a change in consciousness. The cardiovascular effects may include hypotension (low blood pressure) and various cardiac rhythm disorders such as sinus bradycardia (slow regular heart rhythm), bradyarrhythmia (slow irregular heart rhythm) and partial or complete atrioventricular block.Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins. 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 in order 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.