Andromedotoxin

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 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. 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. Ac = acetyl 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 principle toxic isoforms. Different Rhododendron species contain multiple different grayanotoxin isoforms, contributing to differences in plant toxicity. 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). Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine. Experiments utilizing squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron. 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. Due to its transient ability to activate channels and increase membrane permeability to sodium ions, grayanotoxin is classified as a reversible Nav1.x agonist. 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. Other early-onset symptoms may include diplopia and blurred vision, dizziness, hypersalivation, perspiration, weakness 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 and/or ST-segment elevations as seen in ischemic myocardial threat, and nodal rhythm or Wolff-Parkinson-White syndrome.