Batrachotoxin

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Batrachotoxin
Skeletal formula of batrachotoxin
Ball-and-stick model of batrachotoxin
Identifiers
CAS number 23509-16-2 YesY
PubChem 31958
ChemSpider 10310314 YesY
Jmol-3D images Image 1
Properties
Molecular formula C31H42N2O6
Molar mass 538.67 g mol−1
Density 1.304 g/mL [1]
Hazards
Main hazards Highly toxic
LD50 0.002–0.007 mg/kg
(estimated, human, sub-cutaneous)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Batrachotoxins (BTX) are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs (poison dart frog), melyrid beetles, and birds (Pitohui, Ifrita kowaldi, Colluricincla megarhyncha). Batrachotoxin was derived from the Greek word "batrachos" meaning "frog". [2]

History[edit]

It was named by scientists John Daly and Bernhard Witkop, who separated the potent toxic alkaloids fraction and determined chemical properties. Due to the difficulty of handling such a potent toxin and the minuscule amount that could be collected, a comprehensive structure determination involved several difficulties. However, Takashi Tokuyama, who joined to the investigation later, converted one of the congener compounds, Batrachotoxinin A, to a crystalline derivative and its unique steroidal structure was solved with x-ray diffraction techniques (1968).[3] When the mass spectrum and NMR spectrum of batrachotoxin and the batrachotoxinin A derivatives were compared, it was realized that the two shared the same steroidal structure and that batrachotoxin was batrachotoxinin A with a single extra pyrrole moiety attached. The structure of batrachotoxin was established in 1969 through chemical recombination of both fragments.[4] Batrachotoxinin A was synthesized by Michio Kurosu, Lawrence R. Marcin, Timothy J. Grinsteiner, and Yoshito Kishi in 1991.[5]

Recently in 2012, A. Sloan Devlin and J. Du Bois developed methods for producing the pentacyclic core of batrachotoxin and its analogues through using Diels-Alder cycloaddition of ring-strained dienophiles and an intermediate furan. [6]

Toxicity[edit]

Extrapolating from the 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 colourless 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[7] involved in action potential generation and by modifying both their ion selectivity and voltage sensitivity. Batrachotoxin (BTX) irreversibly binds to the Na+ channel receptors which causes a conformational change in the channels that forces the sodium channels to remain open. Interestingly, Batrachotoxin not only keeps voltage-gated sodium channels open, but it also reduces the single-channel conductance. In other words, the toxin binds to the sodium channel and keeps the membrane permeable to sodium ions in an all or none manner. [8]

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.

In layman's terms, batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells such that they cannot reset. The neuron is no longer capable of 'firing' (sending messages) and this results in paralysis.

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 toxic 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 °C (99 °F). Its activity is also more rapid at an alkaline pH, which suggests that the unprotonated form may be more active.

Treatment[edit]

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.

Sources[edit]

The "poison dart" (or "poison arrow") frog does not produce batrachotoxin itself. It is believed that the frogs get the poison from eating beetles or other insects in their native habitat. Frogs raised in captivity do not produce batrachotoxin, and thus may be handled without risk.

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, which generally contains 27 times more batrachotoxin than its close relatives and is 20-fold more toxic.

Also in 1990, it was discovered that some bird species in New Guinea, such as the Hooded Pitohui, contain the toxin on their skin and feathers. The Ifrita kowaldi and Pitohui dichrous are two species of birds known to have developed an efficient storage of batrachotoxins in the integument of their skin and feathers. While the purpose for toxicity in these birds is unknown, the presence of batrachotoxins in these birds species is a remarkable example of convergent evolution. Like the dart frogs, it is believed these birds ingest the toxin from a food source, batrachotoxin-containing insects, and then secrete it.[9] Specifically, the toxin has been recently discovered in melyrid beetles from New Guinea (the genus Choresine),[10] making them the likely source of the toxin in the birds that consume them.[11]

Use[edit]

See also: Arrow poison and Blowdart

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 Amerindians by first impaling a frog on a piece of wood.[12] 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 their lethal power for up to a year.

See also[edit]

  • Tetrodotoxin, a toxin that works in the opposite way of batrachotoxin

Notes[edit]

  1. ^ Daly, J. W.; Journal of the American Chemical Society 1965, V87(1), P124-6 CAPLUS
  2. ^ The Merck Index. Entry 1009 Page 167
  3. ^ Tokuyama, T.; Daly, J.; Witkop, B.; Karle, I. L.; Karle, J. (1968). "The structure of Batrachotoxinin A, a novel steroidal alkaloid from the Columbian arrow poison frog, Phyllobates aurotaenia". J. Am. Chem. Soc. 90 (7): 1917–1918. doi:10.1021/ja01009a052. 
  4. ^ Tokuyama, T.; Daly, J.; Witkop, B. (1969). "Structure of Batrachotoxin, a steroidal alkaloid from the Colombian arrow poison frog, Phyllobates aurotaenia, and partial synthesis of Batrachotoxin and its analogs and homologs". J. Am. Chem. Soc. 91 (14): 3931–3933. doi:10.1021/ja01042a042. 
  5. ^ Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. (1998). "Total Synthesis of (±)-Batrachotoxinin A". J. Am. Chem. Soc. 120 (26): 6627–6628. doi:10.1021/ja981258g. 
  6. ^ Devlin, A. Sloan;Du Bois, J.; (2013). "Modular synthesis of the pentacyclic core of batrachotoxin and select batrachotoxin analogue designs". Chem. Sci. 4: 1059. 
  7. ^ Wang, S. Y.; Mitchell, J.; Tikhonov, D. B.; Zhorov, B. S.; Wang, G. K. (2006). "How Batrachotoxin modifies the sodium channel permeation pathway: Computer modeling and site-directed mutagenesis". Mol. Pharmacol. 69 (3): 788–795. doi:10.1124/mol.105.018200. PMID 16354762. 
  8. ^ Wang, S. Y.; Tikhonov, Denis B.; Mitchell, Jane; Zhorov, Boris S.; Wang, Ging Kuo (2007). "Irreversible Block of Cardiac Mutant Na+ Channels by Batrachotoxin Channels". Channels 1 (3). 
  9. ^ Maksim V. Plikus, Maksim V.; Astrowski, Alaiksandr A.; (2014). "Deadly hairs, lethal feathers – convergent evolution of poisonous integument in mammals and birds". Experimental Dermatology 23: 466–468. doi:10.1111/exd.12408. 
  10. ^ Dumbacher, J. P.; Wako, A.; Derrickson, S. R.; Samuelson, A.; Spande, T. F.; Daly, J. W. (2004). "Melyrid beetles (Choresine): A putative source for the Batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds". Proc. Natl. Acad. Sci. U.S.A. 101 (45): 15857–15860. doi:10.1073/pnas.0407197101. PMC 528779. PMID 15520388. 
  11. ^ "Academy Research: A Powerful Poison". California Academy of Science. 
  12. ^ Crump, M. (2000). In Search of the Golden Frog. University Of Chicago Press. p. 12. ISBN 978-0226121987. 

General references[edit]

  • Daly, J. W.; Witkop, B. (1971). "Chemistry and Pharmacology of Frog Venoms". In Bücherl, W.; Buckley, E. E.; Deulofeu, V. Venomous Animals and their Venoms 2. New York: Academic Press. LCCN 66014892.