Batrachotoxin

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Batrachotoxin
Skeletal formula of batrachotoxin
Ball and stick model of batrachotoxin
Names
Other names
3α,9α-epoxy-14β,18-(2′-oxyethyl-N-methylamino)-5β-pregna-7,16-diene-3β,11α,20α-triol 20α-2,4-dimethylpyrrole-3-carboxylate
Identifiers
3D model (JSmol)
ChemSpider
Properties
C31H42N2O6
Molar mass 538.68 g·mol−1
Density 1.304 g/mL [1]
Hazards
Main hazards Highly toxic
Lethal dose or concentration (LD, LC):
2 μg/kg
(mouse, sub-cutaneous)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. Batrachotoxin was derived from the Greek word βάτραχος bátrachos "frog".[2] Structurally-related chemical compounds are often referred to collectively as batrachotoxins. It is the most poisonous alkaloid on earth. In frogs, the alkaloid is present mostly on the skin. Frogs cannot synthesize batrachotoxin themselves, instead adult frogs must obtain the alkaloid from insects and other invertebrates in their diet. In some species, mother frogs will feed alkaloid-laden unfertilized eggs to their tadpoles in order to confer the toxin to them before they are mature enough to hunt on their own.

History[edit]

It was named by scientists John W. Daly and Bernhard Witkop, who separated the potent toxic alkaloids fraction and determined its chemical properties. They isolated four major toxic steroidal alkaloids including batrachotoxin, isobatrachotoxin, pseudobatrachotoxin, and batrachotoxinin A.[3] 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 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).[4] 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. In fact, batrachotoxin was able to be partially hydrolyzed using sodium hydroxide into a material with identical TLC and color reactions as batrachotoxinin A.[3] The structure of batrachotoxin was established in 1969 through chemical recombination of both fragments.[3] Batrachotoxinin A was synthesized by Michio Kurosu, Lawrence R. Marcin, Timothy J. Grinsteiner, and Yoshito Kishi in 1998.[5]

Toxicity[edit]

According to experiments with rodents, batrachotoxin is one of the most potent alkaloids known: its subcutaneous LD50 in mice is  2 µg/kg.[6] Meanwhile, its derivative, batrachotoxinin A, has a much lower toxicity with an LD50 of 1000 µg/kg.[3]

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+ channels which causes a conformational change in the channels that forces the sodium channels to remain open. 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.

Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevent them from closing. The neuron can no longer send signals 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")[citation needed]. 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]

Batrachotoxin has been found in the four Papuan beetle species C. pulchra, C. semiopaca, C. rugiceps and C. sp. A, which are all in the genus Choresine in the family Melyridae.[9][10]

Several species of bird endemic to New Guinea have the toxin in their skin and on their feathers: the Blue-capped ifrit (Ifrita kowaldi), Little shrikethrush (aka rufous shrike-thrush, Colluricincla megarhyncha), and the following Pitohui species: the Hooded pitohui (Pitohui dichrous, which is the most toxic of the birds), Crested pitohui (Ornorectes cristatus), Black pitohui (Melanorectes nigrescens),[11] Rusty pitohui (Pseudorectes ferrugineus), and Variable pitohui.[12] Since the study was done, the Variable pitohui has been split into three species: the Northern variable pitohui (Pitohui kirhocephalus), Raja Ampat pitohui (Pitohui cerviniventris), and Southern variable pitohui (Pitohui uropygialis).[13]

While the purpose for toxicity in these birds is not certain, the presence of batrachotoxins in these species is an example of convergent evolution. It is believed that these birds gain the toxin from batrachotoxin-containing insects that they eat, and then secrete it through the skin.[10][14]

Batrachotoxin has also been found in a few Colombian Frog species: Golden poison frog (Phyllobates terribilis), Black-legged poison frog (Phyllobates bicolor), and Kokoe poison frog (Phyllobates aurotaenia).[9][10] The Kokoe poison frog used to include Phyllobates sp. aff. aurotaenia, but it has recently been recognized as a distinct species. All four of those frog species are in the Poison dart frog family. Of the four, the most toxic is the most recently discovered golden poison frog, which generally contains 27 times more batrachotoxin than its close relatives and is 20-fold more toxic.

The frogs do not produce batrachotoxin themselves. Just as in the birds, it is believed that these frogs gain the toxin from batrachotoxin-containing insects that they eat, and then secrete it through the skin.[10] Beetles in the genus Choresine are not found in Colombia, but it is thought that the frogs might get the toxin from beetles in other genera within the family Melyridae, which could be found in Colombia.[9]

Frogs raised in captivity do not produce batrachotoxin, and thus may be handled without risk. However, this limits the amount of batrachotoxin available for research as 10,000 frogs yielded only 180 mg of batrachotoxin.[15] As these frogs are endangered, their harvest is unethical. Biosynthetic studies are also challenged by the slow rate of synthesis of batrachotoxin.[3]

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.

Use[edit]

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

Poison darts are prepared by the Chocó by first impaling a frog on a piece of wood.[16] 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. ^ a b c d e 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.
  4. ^ 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.
  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. ^ Tokuyama, T.; Daly, J.; Witkop, B. (1969). "The 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): 3931–3938. doi:10.1021/ja01009a052.
  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. ^ a b c 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.
  10. ^ a b c d 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 (7): 466–468. doi:10.1111/exd.12408.
  11. ^ Avian chemical defense: Toxic birds not of a feather
  12. ^ Dumbacher, J.; Beehler, B.; Spande, T.; Garraffo, H.; Daly, J. (1992). "Homobatrachotoxin in the genus Pitohui: chemical defense in birds?". Science. 258 (5083): 799–801. Bibcode:1992Sci...258..799D. doi:10.1126/science.1439786. PMID 1439786.
  13. ^ Gill, F.; Donsker, D., eds. (2017). "Orioles, drongos & fantails". IOC World Bird List (v 7.2). Retrieved 10 June 2017.
  14. ^ "Academy Research: A Powerful Poison". California Academy of Science.
  15. ^ Du Bois, Justin, et al., inventor; Board of Trustees of the Leland Standford Junior University, assignee. Batrachotoxin Analogues, Compositions, Uses, and Preparation Thereof. US patent 2014/0171410 A1. June 19, 2014.
  16. ^ 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.