Batrachotoxin
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3D model (JSmol)
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IUPHAR/BPS
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InChI
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InChI=1S/C31H42N2O6/c1-18-16-32-19(2)25(18)26(35)38-20(3)22-8-9-30-23-7-6-21-14-29(36)11-10-27(21,4)31(23,39-29)24(34)15-28(22,30)17-33(5)12-13-37-30/h7-8,16,20-21,24,32,34,36H,6,9-15,17H2,1-5H3/t20-,21+,24+,27-,28-,29+,30-,31-/m0/s1 Y
Key: ISNYUQWBWALXEY-OMIQOYQYSA-N Y
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InChI=1/C31H42N2O6/c1-18-16-32-19(2)25(18)26(35)38-20(3)22-8-9-30-23-7-6-21-14-29(36)11-10-27(21,4)31(23,39-29)24(34)15-28(22,30)17-33(5)12-13-37-30/h7-8,16,20-21,24,32,34,36H,6,9-15,17H2,1-5H3/t20-,21+,24+,27-,28-,29+,30-,31-/m0/s1
Key: ISNYUQWBWALXEY-OMIQOYQYBY
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SMILES
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CC1=CNC(=C1C(=O)OC(C)C2=CC[C@@]34C2(C[C@H](C56C3=CC[C@H]7[C@@]5(CC[C@@](C7)(O6)O)C)O)CN(CCO4)C)C
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Chemical formula
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C31H42N2O6 |
| Molar mass |
538.68 g·mol−1 |
| Density |
1.304 g/mL [1] |
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Highly toxic |
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LD50 (median dose)
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2 μg/kg
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of frogs (poison dart frog), melyrid beetles, and birds (the pitohui, blue-capped ifrit, and little shrikethrush). Batrachotoxin was derived from the Greek word βάτραχος bátrachos "frog".[2] Structurally-related chemical compounds are often referred to collectively as batrachotoxins.
Contents
- 1 History
- 2 Toxicity
- 3 Treatment
- 4 Sources
- 5 Use
- 6 See also
- 7 Notes
- 8 General references
History
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
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. 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.
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
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
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. However, this limits the amount of batrachotoxin available for research as 10,000 frogs yielded only 180 mg of batrachotoxin.[9] 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.
Of the three so-called "poison dart" frogs which contain batrachotoxin—golden poison frog, Kokoe poison frog, and neari—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.
Nine species of bird endemic to New Guinea (including the hooded pitohui and three other Pitohui species) have the toxin in their skin and on their feathers. The blue-capped ifrit and hooded pitohui 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 not certain, the presence of batrachotoxins in these species is an example of convergent evolution. Just as in the dart frogs, it is believed that these birds gain the toxin from batrachotoxin-containing insects that they eat, and then secrete it through the skin.[10] Specifically, batrachotoxin has been found in melyrid beetles from New Guinea (the genus Choresine),[11] making them a likely source of the toxin in the birds, if they are consumed.[12]
Use
See also: Arrow poison and Blowgun
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.[13] 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
- Tetrodotoxin, a toxin that works in the opposite way of batrachotoxin
Notes
- ^ Daly, J. W.; Journal of the American Chemical Society 1965, V87(1), P124-6 CAPLUS
- ^ The Merck Index. Entry 1009 Page 167
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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).
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "Academy Research: A Powerful Poison". California Academy of Science.
- ^ Crump, M. (2000). In Search of the Golden Frog. University Of Chicago Press. p. 12. ISBN 978-0226121987.
General references
- 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.
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Neurotoxins
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| Animal |
- Batrachotoxin
- Bestoxin
- Birtoxin
- Bungarotoxin
- Charybdotoxin
- Conotoxin
- Fasciculin
- Huwentoxin
- Poneratoxin
- Saxitoxin
- Tetrodotoxin
- Vanillotoxin
- Spooky toxin (SsTx)
- Epibatidine
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| Bacterial |
- Botulinum toxin
- Tetanospasmin
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| Cyanobacteria |
- Anatoxin-a
- Anatoxin-a(S)
- BMAA
- Saxitoxin
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| Plant |
- Bicuculline
- Penitrem A
- Picrotoxin
- Strychnine
- Tutin
- Rotenone
- Ginkgotoxin
- Cicutoxin
- Oenanthotoxin
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| Pesticides |
- Fenpropathrin
- Tetramethylenedisulfotetramine
- Bromethalin
- Crimidine
- Methamidophos
- Endosulfan
- Fipronil
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| Nerve agents |
- Cyclosarin
- EA-3148
- Novichok agent
- Sarin
- Soman
- Tabun
- VE
- VG
- VM
- VR
- VX
- GV
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| Other |
- Dimethylmercury
- Toxopyrimidine
- TBPS
- IPTBO
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