Batrachotoxin

Batrachotoxins are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs (poison dart frog), Melyridae beetles and birds (Pitohui, Ifrita kowaldi).

Chemistry
There are several types of batrachotoxins; batrachotoxin itself has the structure shown on the right.

Batrachotoxin comes from the Greek words "batrachos (βάτραχος)", meaning frog, and "toxine (τοξίνη)", meaning poison. It was named by scientists John Daly and Bernard Witkop, who isolated the pure alkaloid and determined its structure and chemical properties. Its chemical formula is C31H42N2O6.

More than 100 toxins have been identified from the skin secretions of members of the Dendrobatidae family of frogs, especially Dendrobates and Phyllobates. Members of the genus Dendrobates (of which there are at least 44 known species) are also known as "poison dart" or "poison arrow" frogs. However, only frogs of the genus Phyllobates produce the super-deadly batrachotoxin.

Toxicity
Batrachotoxin is one of the most potent toxins known. Extrapolating from the lethal dosage LD50 in rats, the lethal dose of this alkaloid in humans is estimated to be 1 to 2 µg/kg. Thus, the lethal dose for a 68 kg (150 pound) person would be approximately 100 micrograms, or equivalent to the weight of two grains of ordinary (fine) table salt (NaCl). Batrachotoxin is thus around fifteen times more potent than curare (another arrow poison used by South American Indians and derived from plants of the genera Strychnos and Curarea), and about ten times more potent than tetrodotoxin, from the puffer fish.

The toxin is released through colorless or milky secretions from glands located on the back and behind the ears of frogs from the genus Phyllobates. When one of these frogs is agitated, feels threatened or is in pain, the toxin is reflexively released through several canals.

As a neurotoxin it affects the nervous system. Neurological function depends on depolarization of nerve and muscle fibres due to increased sodium ion permeability of the excitable cell membrane. Lipid-soluble toxins such as batrachotoxin act directly on sodium ion channels involved in action potential generation and by modifying both their ion selectivity and voltage sensitivity.

This has a direct effect on the peripheral nervous system (PNS). Batrachotoxin in the PNS produces increased permeability (selective and irreversible) of the resting cell membrane to sodium ions, without changing potassium or calcium concentration. This influx of sodium depolarizes the formerly polarized cell membrane. Batrachotoxin also alters the ion selectivity of the ion channel by increasing the permeability of the channel toward larger cations. Voltage-sensitive sodium channels become persistently active at the resting membrane potential. Batrachotoxin kills by permanently blocking nerve signal transmission to the muscles.

Although generally classified as a neurotoxin, batrachotoxin has marked effects on heart muscles. These effects are similar to the cardiotoxic effects of digitalis (digoxin), a poison found in the foxglove plant. Batrachotoxin interferes with heart conduction, causing arrhythmias, extrasystoles, ventricular fibrillation and other changes which lead to cardiac arrest. Batrachotoxin induces a massive release of acetylcholine in nerves and muscles and destruction of synaptic vesicles, as well. Batrachotoxin R is more effective than related batrachotoxin A.

Structural changes in nerves and muscles are due to a massive influx of sodium ions, which produces osmotic alterations. It has been suggested that there may also be an effect on the central nervous system, although it is not currently known what such an effect may be.

Batrachotoxin activity is temperature-dependent, with a maximum activity at 37 degrees Celsius (98.6 degrees Fahrenheit). Its activity is also more rapid at an alkaline pH, which suggests that the unprotonated form may be more active.

Treatment
Currently no effective antidote exists for the treatment of batrachotoxin poisoning. Veratridine, aconitine and grayanotoxin - like batrachotoxin - are lipid-soluble poisons which similarly alter the ion selectivity of the sodium channels, suggesting a common site of action. Due to these similarities, treatment for batrachotoxin poisoning might best be modeled after, or based on, treatments for one of these poisons. Treatment may also be modeled after that for digitalis, which produces somewhat similar cardiotoxic effects.

While it is not an antidote, the membrane depolarization can be prevented or reversed by either tetrodotoxin (from puffer fish), which is a noncompetitive inhibitor, or saxitoxin ("red tide"). These both have effects antagonistic to those of batrachotoxin on sodium flux. Certain anesthetics may act as receptor antagonists to the action of this alkaloid poison, while other local anesthetics block its action altogether by acting as competitive antagonists.

Source
The "poison dart" (or "poison arrow") frog does not produce batrachotoxin itself. It is believed that the frogs get the poison from eating ants or other insects in their native habitat, and the insects obtain the poison from a plant source. The toxin has been recently discovered in beetles, making them the likely source of the toxin in birds and frogs. Frogs raised in captivity do not produce batrachotoxin, and thus may be handled without the risk of death.

The native habitat of poison dart frogs is the warm regions of Central America and South America in which the humidity is around 80 percent.

Of the three so-called "poison dart" frogs which contain batrachotoxin - Phyllobates terribilis, Phyllobates aurotaenia, and Phyllobates bicolor - the most toxic is the most recently discovered Phyllobates terribilis.

Phyllobates terribilis produces 27 times more batrachotoxin than its close relatives and is 20-fold more toxic. One freshly caught frog has up to 2 milligrams of toxin, or 50 times the lethal dose in humans.

Use
The most common use of this toxin is by the Noanamá Chocó and Emberá Chocó Indians of western Colombia for poisoning blowgun darts for use in hunting.

Poison darts are prepared by the Chocó Indians by first impaling a frog on a piece of wood. By some accounts, the frog is then held over or roasted alive over a fire until it cries in pain. Bubbles of poison form as the frog's skin begins to blister. The dart tips are prepared by touching them to the toxin, or the toxin can be caught in a container and allowed to ferment. Poison darts made from either fresh or fermented batrachotoxin are enough to drop monkeys and birds in their tracks. Nerve paralysis is almost instantaneous.

Other accounts say that a stick siurukida ("bamboo tooth") is put through the mouth of the frog and passed out through one of its hind legs. This causes the frog to perspire profusely on its back, which becomes covered with a white froth. The darts are dipped or rolled in the froth, preserving its destructive power for up to a year.