Batrachotoxin (BTX)
Background and History:
- The word "toxin" stems from the Greek word "taxon" or "bow" in reference to the poisoned arrows used in Greek warfare, demonstrating what an old practice the use of toxins in warfare really is. [15]
- Batrachotoxin is produced by a genus of birds native of New Ginea, and Indonesia, as well as Phyllobates dart frogs which are indigenous to Colombia. Both obtain their toxicity from their diets of Melyrid beetles, then secrete batrachotoxin from the skin. For this reason, frogs kept in captivity quickly lose their toxicity due to the change in diet. [5]
- Toxicity of the Phyllobates varies among species, but the most toxic is the golden tree frog, whose secretions have an LD50 of 2.0μl/kg in mice. [7]
- Lethal doses as low as 0.01μL/kg have been recorded. [11]
- Batrachotoxin was and still is used primarily for hunting by indigenous peoples of South America, especially in Colombia, but there are records of batrachotoxin being used in tribal warfare. [2]
- According to early explorers of South America, paralysis was so immediate that birds hit with blow darts containing batrachotoxin drop out of the air.[3]
- Magellan was likely killed by a batrachotoxin-laced dart in the Philippines, where tribes are known to use the toxins produced by birds on their weapons. [8]
- As of today, use of batrachotoxin as an agent of biochemical warfare is very unlikely due to the small quantities that frogs can produce at one time, however, the toxins are easily synthesized in a lab and have a long shelf life. [4]
- In order for immediate effects, batrachotoxin must be administered subcutaneously, making it an inefficient weapon of mass harm. It is much more likely to be used as a tool for assassination. However, milder symptoms may arise upon ingestion or just skin contact with batrachotoxin. [7]
Mechanism:
- Batrachotoxin is neurotoxic as well as cardiotoxic. [9],[14]
- Batrachotoxin irreversibly binds to the IVS6 segment of the voltage-gated sodium channels, preventing closure. [12]
- Neurons are unable to return to a resting state, and instead maintain a high intracellular voltage potential.
- When the sodium channels are forced open, they become less selective and allow a larger variety of ions in and out of the cell than they normally would.[13]
- Species of Phyllobates have modified sodium channels and are immune to batrachotoxin. [1]
Fig. 3.
Mechanism of action of batrachotoxin, compared to other toxins. Image Source: [14]
Mechanism of action of batrachotoxin, compared to other toxins. Image Source: [14]
Signs and symptoms:
Exposure to high doses of toxin can lead to nearly immediate death. [3],[7],[12]
Human exposure to batrachotoxin is not common, and therefore little is known about its effects. [12]
Exposure to high doses of toxin can lead to nearly immediate death. [3],[7],[12]
Human exposure to batrachotoxin is not common, and therefore little is known about its effects. [12]
- Neurologic: Paralysis, muscle contractions
- Oral: salivation
- Respiratory: Difficulty breathing (due to paralysis.)
- Cardiovascular: Arrhythmias, fibrillation, cardiac failure
- Dermal: numbness or tingling of effected area.
Treatments:
- There is no known antidote for batrachotoxin poisoning. [11],[16]
- Because of the similar mechanisms of action and chemical properties, it is possible that the same antidotes used for digitalis poisoning may work for people who have been exposed to batrachotoxin.
- A suitable treatment could be exposure to tetrodotoxin, which has the opposite effect but works on the same binding site on the voltage-gated sodium channel as batrachotoxin.
- Both treatments can be found listed in several locations, but none had any supporting evidence or research.
Citations:
[1] Bolívar, W. Lotters, Stefan. (2004). Phyllobates Terribilis. IUCN Red List of Threatened Species. 2014.2. Retrieves 16 April, 2015.
[2] Daly, J., Witkop, B., Bommer, P., Biermann, K. (1965). Batrachotoxin. The active principle of the Colombian poison arrow frog Phyllobates bicolor. J Am Chem Soc. 5;87(1):124-6.
[3] Dendroworks. (2011). The original poison dart frog. Dendro works. Retrieved 17 April, 2015 from http://www.dendroworks.co.uk/indek.php?option+com_content&view=article&id=57.
[4] Du Bois, J. (2013). Modular Synthesis of the Pentacyclic Core of Batrachotoxin and Select Batrachotoxin Analogue Designs. Chem Sci. 4(3):1059-1063.
[5] Dumbacher, J., Wako, A., Derrickson, S., Samuelson, A., Spande, T., Daly, J. (2004). Melyrid beetles (Choresine): A putative source for the batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds. PNAS. 45(101):15857-15860.
[6] Emerson, C., Zakharov, L., Blakemore, P. (2013). Investigation of functionalized alpha-chloroalkyllithiums for a stereospecific reagent-controlled homologation approach to the analgesic alkaloid (-)-epibatidine. Chemistry. 19(48):16342-56.
[7] Franz, G. (1997). Defense Against Toxic Weapons. US Medical Research and Army Materiel Command. 15.
[8] History.com Staff. (2010). Magellan killed in the Philippines. Retrieved 22 April 2015 at http://www.history.com/this-day-in-history/magellan-killed-in-the-philippines.
[9] Honerjager, P., Reiter, M. (1977). The Cardiotoxic Effect of Batrachotoxin. Pharmacol. 299,239-252.
[10] Jiri, P., Wulff, K., Palomeque, M. (1999). Dart Poison Frogs and Their Toxins. Applied Science and Analysis. ISSN 1057-9419.
[11] Jiri, P., Stredab, L. (2002). Breif Review of Natural Nonprotein Neurotoxins. Applied Science and Analysis. ISSN 1057-9419.
[12] Li, H., Hadid, D., Ragsdale, D. (2002). The Batrachotoxin Receptor on the Voltage-Gated Sodium Channel is Guarded by the Channel Activation Gate. Molecular Pharmacology. 61(4):905-912.
[13] Quandt., F., Narahashi, T. (1982). Modification of single Na+ channels by batrachotoxin. Neurobology. 79:6732-6736.
[14] Stevens, M., Peigneur, S., Tytgat, J. (2011). Neurotoxins and their binding areas on voltage-gated sodium channels. Frontiers in Pharmacology. 71(2):1-13.
[15] Toxic [def 1]. (n.d.). Merriam-Webster Online. Retrieved 18 April, 2015 from http://www.merriam-webster.com/dictionary/toxic.
[16] Wang, S., Mitchell, J., Tikhonov, D., Zhorov, B., Wang, G. (2006) How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis. Molecular Pharmacology. 3(69)788-790.
[1] Bolívar, W. Lotters, Stefan. (2004). Phyllobates Terribilis. IUCN Red List of Threatened Species. 2014.2. Retrieves 16 April, 2015.
[2] Daly, J., Witkop, B., Bommer, P., Biermann, K. (1965). Batrachotoxin. The active principle of the Colombian poison arrow frog Phyllobates bicolor. J Am Chem Soc. 5;87(1):124-6.
[3] Dendroworks. (2011). The original poison dart frog. Dendro works. Retrieved 17 April, 2015 from http://www.dendroworks.co.uk/indek.php?option+com_content&view=article&id=57.
[4] Du Bois, J. (2013). Modular Synthesis of the Pentacyclic Core of Batrachotoxin and Select Batrachotoxin Analogue Designs. Chem Sci. 4(3):1059-1063.
[5] Dumbacher, J., Wako, A., Derrickson, S., Samuelson, A., Spande, T., Daly, J. (2004). Melyrid beetles (Choresine): A putative source for the batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds. PNAS. 45(101):15857-15860.
[6] Emerson, C., Zakharov, L., Blakemore, P. (2013). Investigation of functionalized alpha-chloroalkyllithiums for a stereospecific reagent-controlled homologation approach to the analgesic alkaloid (-)-epibatidine. Chemistry. 19(48):16342-56.
[7] Franz, G. (1997). Defense Against Toxic Weapons. US Medical Research and Army Materiel Command. 15.
[8] History.com Staff. (2010). Magellan killed in the Philippines. Retrieved 22 April 2015 at http://www.history.com/this-day-in-history/magellan-killed-in-the-philippines.
[9] Honerjager, P., Reiter, M. (1977). The Cardiotoxic Effect of Batrachotoxin. Pharmacol. 299,239-252.
[10] Jiri, P., Wulff, K., Palomeque, M. (1999). Dart Poison Frogs and Their Toxins. Applied Science and Analysis. ISSN 1057-9419.
[11] Jiri, P., Stredab, L. (2002). Breif Review of Natural Nonprotein Neurotoxins. Applied Science and Analysis. ISSN 1057-9419.
[12] Li, H., Hadid, D., Ragsdale, D. (2002). The Batrachotoxin Receptor on the Voltage-Gated Sodium Channel is Guarded by the Channel Activation Gate. Molecular Pharmacology. 61(4):905-912.
[13] Quandt., F., Narahashi, T. (1982). Modification of single Na+ channels by batrachotoxin. Neurobology. 79:6732-6736.
[14] Stevens, M., Peigneur, S., Tytgat, J. (2011). Neurotoxins and their binding areas on voltage-gated sodium channels. Frontiers in Pharmacology. 71(2):1-13.
[15] Toxic [def 1]. (n.d.). Merriam-Webster Online. Retrieved 18 April, 2015 from http://www.merriam-webster.com/dictionary/toxic.
[16] Wang, S., Mitchell, J., Tikhonov, D., Zhorov, B., Wang, G. (2006) How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis. Molecular Pharmacology. 3(69)788-790.