Batrachotoxin: Difference between revisions

| Watchedfields = change

| verifiedrevid = 461341190

| ImageFile=Batrachotoxin skeletal.svg

| ImageSize=250

| ImageAlt = Skeletal formula of batrachotoxin

| ImageCaption = [[Skeletal formula]] of batrachotoxin

| ImageFile1 = Batrachotoxin-skeleton-based-on-xtal-3D-st.png

| ImageSize1 = 250

| ImageAlt1 = Stick model of the batrachotoxin molecule

| ImageCaption1 = [[Ball-and-stick model|Stick model]] of batrachotoxin based on the [[crystal structure]] of batrachotoxinin A ''O''-''p''-bromobenzoate<ref name="Karle&Karle1969">{{ cite journal | title = The structural formula and crystal structure of the ''O''-''p''-bromobenzoate derivative of batrachotoxinin A, C₃₁H₃₈NO₆Br, a frog venom and steroidal alkaloid | first1 = I. L. | last1 = Karle | author-link1 = Isabella Karle | first2 = J. | last2 = Karle | author-link2 = Jerome Karle | journal = [[Acta Crystallographica|Acta Crystallogr. B]] | year = 1969 | volume = 25 | issue = 3 | pages = 428–434 | doi = 10.1107/S056774086900238X | pmid = 5820223 | bibcode = 1969AcCrB..25..428K | s2cid = 28609553 }}</ref>

| ImageFile2 = Batrachotoxin-based-on-xtal-3D-bs.png

| ImageSize2 = 250

| ImageAlt2 = Ball-and-stick model of the batrachotoxin molecule

| ImageCaption2 = [[Ball-and-stick model]] of batrachotoxin, as above<ref name="Karle&Karle1969" />

| IUPACName=

| OtherNames= 3α,9α-epoxy-14β,18-(2{{prime}}-oxyethyl-''N''-methylamino)-5β-pregna-7,16-diene-3β,11α,20α-triol 20α-2,4-dimethylpyrrole-3-carboxylate<!-- doi:10.1016/S0099-9598(08)60136-4 -->

|

CASNo_Ref = {{cascite|correct|??}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = TSG6XHX09R

| PubChem= 6324647

| SMILES= Cc1c[nH]c(C)c1C(=O)O[C@@H](C)C1=CC[C@@]23OCCN(C)C[C@@]12C[C@@H](O)[C@]12O[C@]4(O)CC[C@@]1(C)[C@H](CC=C23)C4

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 10310314

| 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

| InChIKey = ISNYUQWBWALXEY-OMIQOYQYBY

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = ISNYUQWBWALXEY-OMIQOYQYSA-N

| C=31 | H=42 | N=2 | O=6

| Appearance=

| Density= 1.304 g/mL<ref>{{cite journal |last1=Daly |first1=J. W. |last2=Witkop |first2=B. |last3=Bommer |first3=P. |last4=Biemann |first4=K. |title=Batrachotoxin. The Active Principle of the Colombian Arrow Poison Frog, Phyllobates bicolor |journal=Journal of the American Chemical Society |date=January 1965 |volume=87 |issue=1 |pages=124–126 |doi=10.1021/ja01079a026 |pmid=5826972 }}</ref>

| MeltingPt=

| BoilingPt=

| Solubility=

| MainHazards= Highly toxic

| FlashPt=

| AutoignitionPt =

| LD50 = /kg<br />(, sub-cutaneous)

'''''' ('''BTX''') extremely potent [[cardiotoxic]] and [[neurotoxic]] [[]] [[]] found in certain species of frogs [[ dart frog]] [[|]] and [[]] [[ ]] [[ ]] known.

====

Batrachotoxin was discovered by Fritz Märki and [[Bernhard Witkop]], at the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, [[Bethesda, Maryland]], U.S.A. Märki and Witkop separated the potent toxic alkaloids fraction from ''[[Phyllobates bicolor]]'' and determined its chemical properties in 1963.<ref>{{cite journal |last1=Märki |first1=F. |last2=Witkop |first2=B. |title=The venom of the Colombian arrow poison frog ''Phyllobates bicolor'' |journal=Experientia |date=July 1963 |volume=19 |issue=7 |pages=329–338 |doi=10.1007/BF02152303 |pmid=14067757 |s2cid=19663576 }}</ref> They isolated four major toxic steroidal alkaloids including batrachotoxin, isobatrachotoxin, pseudobatrachotoxin, and batrachotoxinin A.<ref name=":0" /> 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 (chemistry)|congener]] compounds, batrachotoxinin A, to a crystalline derivative and its unique steroidal structure was solved with [[x-ray diffraction]] techniques (1968).<ref>{{cite journal |last1=Tokuyama |first1=Takashi |last2=Daly |first2=John |last3=Witkop |first3=B. |last4=Karle |first4=Isabella L. |last5=Karle |first5=J. |title=The structure of batrachotoxinin A, a novel steroidal alkaloid from the Columbian arrow poison frog, Phyllobates aurotaenia |journal=Journal of the American Chemical Society |date=March 1968 |volume=90 |issue=7 |pages=1917–1918 |doi=10.1021/ja01009a052 |pmid=5689118 }}</ref> 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 (chemistry)|moiety]] attached. In fact, batrachotoxin was able to be partially [[hydrolyze]]d using [[sodium hydroxide]] into a material with identical TLC and color reactions as batrachotoxinin A.<ref name=":0" /> The structure of batrachotoxin was established in 1969 through chemical recombination of both fragments.<ref name=":0">{{cite journal |last1=Tokuyama |first1=Takashi |last2=Daly |first2=J. |last3=Witkop |first3=B. |title=Structure of batrachotoxin, a steroidal alkaloid from the Colombian arrow poison frog, phyllobates aurotaenia, and partial synthesis of batrachotoxin and its analogs and homologs |journal=Journal of the American Chemical Society |date=1 July 1969 |volume=91 |issue=14 |pages=3931–3938 |doi=10.1021/ja01042a042 |pmid=5814950 }}</ref> Batrachotoxinin A was synthesized by Michio Kurosu, Lawrence R. Marcin, Timothy J. Grinsteiner, and [[Yoshito Kishi]] in 1998.<ref>{{cite journal |last1=Kurosu |first1=Michio |last2=Marcin |first2=Lawrence R. |last3=Grinsteiner |first3=Timothy J. |last4=Kishi |first4=Yoshito |title=Total Synthesis of (±)-Batrachotoxinin A |journal=Journal of the American Chemical Society |date=July 1998 |volume=120 |issue=26 |pages=6627–6628 |doi=10.1021/ja981258g }}</ref>

According to experiments with [[rodent]]s, batrachotoxin is one of the most potent alkaloids known: its [[Intravenous therapy|intravenous]] {{LD50}} in mice is 2–3&nbsp;μg/kg.<ref>{{cite journal |last1=Tokuyama |first1=Takashi |last2=Daly |first2=John |last3=Witkop |first3=B. |last4=Karle |first4=Isabella L. |last5=Karle |first5=J. |title=The structure of batrachotoxinin A, a novel steroidal alkaloid from the Columbian arrow poison frog, ''Phyllobates aurotaenia'' |journal=Journal of the American Chemical Society |date=March 1968 |volume=90 |issue=7 |pages=1917–1918 |doi=10.1021/ja01009a052 |pmid=5689118 }}</ref> Meanwhile, its derivative, batrachotoxinin A, has a much lower toxicity with an {{LD50}} of 1000&nbsp;μg/kg.<ref name=":0" />

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.

Batrachotoxin activity is temperature-dependent, with a maximum activity at {{convert|37|C|F}}. Its activity is also more rapid at an [[alkaline]] pH, which suggests that the unprotonated form may be more active.

=== Neurotoxicity ===

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 channel]]s<ref name="pmid16354762">{{cite journal |last1=Wang |first1=Sho-Ya |last2=Mitchell |first2=Jane |last3=Tikhonov |first3=Denis B. |last4=Zhorov |first4=Boris S. |last5=Wang |first5=Ging Kuo |title=How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis |journal=Molecular Pharmacology |date=March 2006 |volume=69 |issue=3 |pages=788–795 |doi=10.1124/mol.105.018200 |pmid=16354762 |s2cid=6343011 }}</ref> involved in [[action potential]] generation and by modifying both their ion selectivity and voltage sensitivity. Batrachotoxin 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 ion channel|voltage-gated]] sodium channels open but also reduces 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.<ref>{{cite journal |last1=Wang |first1=Sho-Ya |last2=Tikhonov |first2=Denis B. |last3=Mitchell |first3=Jane |last4=Zhorov |first4=Boris |last5=Wang |first5=Ging Kuo |title=Irreversible Block of Cardiac Mutant Na + Channels by Batrachotoxin |journal=Channels |date=23 May 2007 |volume=1 |issue=3 |pages=179–188 |doi=10.4161/chan.4437 |pmid=18690024 |doi-access=free }}</ref>

Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells . The neuron no longer and this results in paralysis.

=== Cardiotoxicity ===

Although generally classified as a [[neurotoxin]], batrachotoxin has marked effects on [[heart muscle]]s and its effects are mediated through sodium channel activation. Heart conduction is impaired resulting in [[Heart arrhythmia|arrhythmia]]s, [[extrasystole]]s, [[ventricular fibrillation]] and other changes which lead to [[asystole]] and [[cardiac arrest]]. Batrachotoxin induces a massive release of [[acetylcholine]] in nerves and muscles and destruction of [[synaptic vesicle]]s, as well.{{Citation needed|date=November 2021}} Batrachotoxin R is more toxic than related batrachotoxin A.{{Citation needed|date=November 2021}}

==Treatment==

{{More citations needed|section|date=November 2022}}

Currently, no effective [[antidote]] exists for the treatment of batrachotoxin poisoning.<ref name=":1">{{cite book |doi=10.1016/B978-0-12-386454-3.00984-2 |chapter=Animals, Poisonous and Venomous |title=Encyclopedia of Toxicology |date=2014 |last1=Dodd-Butera |first1=T. |last2=Broderick |first2=M. |pages=246–251 |isbn=978-0-12-386455-0 }}</ref> [[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]]<ref name=":1" /> (from [[puffer fish]]), which is a [[noncompetitive inhibitor]], or [[saxitoxin]] ("[[red tide]]").{{Citation needed|date=February 2018}} These both have effects antagonistic to those of batrachotoxin on sodium flux. Certain [[anesthetic]]s may act as [[receptor antagonist]]s to the action of this alkaloid poison, while other [[local anesthetic]]s block its action altogether by acting as [[Competitive inhibition|competitive]] antagonists.

==Sources==

Batrachotoxin has been found in four Papuan beetle species, all in the genus ''[[Choresine]]'' in the family [[Melyridae]]; ''[[Choresine pulchra|C. pulchra]]'', ''[[Choresine semiopaca|C. semiopaca]]'', ''[[Choresine rugiceps|C. rugiceps]]'' and [[Choresine sp. A|''C.'' sp. A]].<ref name="pmid15520388">{{cite journal |last1=Dumbacher |first1=John P. |last2=Wako |first2=Avit |last3=Derrickson |first3=Scott R. |last4=Samuelson |first4=Allan |last5=Spande |first5=Thomas F. |last6=Daly |first6=John W. |title=Melyrid beetles (''Choresine''): A putative source for the batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds |journal=Proceedings of the National Academy of Sciences |date=9 November 2004 |volume=101 |issue=45 |pages=15857–15860 |doi=10.1073/pnas.0407197101 |doi-access=free |pmid=15520388 |pmc=528779 }}</ref><ref name="Plikus">{{cite journal |last1=Plikus |first1=Maksim V. |last2=Astrowski |first2=Aliaksandr A. |title=Deadly hairs, lethal feathers – convergent evolution of poisonous integument in mammals and birds |journal=Experimental Dermatology |date=July 2014 |volume=23 |issue=7 |pages=466–468 |doi=10.1111/exd.12408 |pmid=24698054 }}</ref>

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'', the most toxic of the birds), [[crested pitohui]] (''Ornorectes cristatus''), [[black pitohui]] (''Melanorectes nigrescens''),<ref>{{cite journal |last1=Weldon |first1=Paul J. |title=Avian chemical defense: Toxic birds not of a feather |journal=Proceedings of the National Academy of Sciences |date=21 November 2000 |volume=97 |issue=24 |pages=12948–12949 |doi=10.1073/pnas.97.24.12948 |doi-access=free |pmid=11087849 |pmc=34071 }}</ref> [[rusty pitohui]] (''Pseudorectes ferrugineus''), and the variable pitohui,<ref>{{cite journal |last1=Dumbacher |first1=John P. |last2=Beehler |first2=Bruce M. |last3=Spande |first3=Thomas F. |last4=Garraffo |first4=H. Martin |last5=Daly |first5=John W. |title=Homobatrachotoxin in the Genus Pitohui : Chemical Defense in Birds? |journal=Science |date=30 October 1992 |volume=258 |issue=5083 |pages=799–801 |doi=10.1126/science.1439786 |pmid=1439786 }}</ref> which is now split into three species: the [[northern variable pitohui]] (''Pitohui kirhocephalus''), [[Raja Ampat pitohui]] (''P. cerviniventris''), and [[southern variable pitohui]] (''P. uropygialis'').<ref name ="Gill">{{cite web|editor1-last=Gill|editor1-first=F. | editor1-link=Frank Gill (ornithologist) |editor2-last=Donsker|editor2-first=D. |title=Orioles, drongos & fantails| url=http://www.worldbirdnames.org/bow/orioles/|website=IOC World Bird List (v 7.2)|access-date=10 June 2017|date=2017}}</ref>

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.<ref name="Plikus"/><ref name="calacademy.org">{{cite web | url = http://www.calacademy.org/science_now/academy_research/powerful_poison.php | publisher = California Academy of Science | title = Academy Research: A Powerful Poison | access-date = 2013-05-10 | archive-url = https://web.archive.org/web/20120827195307/http://www.calacademy.org/science_now/academy_research/powerful_poison.php | archive-date = 2012-08-27 | url-status = dead }}</ref>

Batrachotoxin has also been found in all described species of the poison dart frog genus ''[[Phyllobates]]'' from [[Nicaragua]] to [[Colombia]], including the [[golden poison frog]] (''Phyllobates terribilis''), [[black-legged poison frog]] (''P. bicolor''), [[lovely poison frog]] (''P. lugubris''), [[Golfodulcean poison frog]] (''P. vittatus''), and [[Kokoe poison frog]] (''P. aurotaenia'').<ref name="pmid15520388"/><ref name="Plikus"/><ref>{{cite journal | doi=10.1111/evo.13672 | title=Does batrachotoxin autoresistance coevolve with toxicity in Phyllobates poison-dart frogs? | year=2019 | last1=Márquez | first1=Roberto | last2=Ramírez-Castañeda | first2=Valeria | last3=Amézquita | first3=Adolfo | journal=Evolution | volume=73 | issue=2 | pages=390–400 | pmid=30593663 | s2cid=58605344 | doi-access=free }}</ref> The Kokoe poison frog used to include [[Phyllobates sp. aff. aurotaenia|''P.'' sp. aff. ''aurotaenia'']], now recognized as distinct. All six of these frog species are in the [[poison dart frog]] family.

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.<ref name="Plikus"/> 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 same family ([[Melyridae]]), several of which are found in Colombia.<ref name="pmid15520388"/>

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&nbsp;mg of batrachotoxin.<ref>Du Bois, Justin, et al., inventor; Board of Trustees of the Leland Stanford Junior University, assignee. Batrachotoxin Analogues, Compositions, Uses, and Preparation Thereof. US patent 2014/0171410 A1. June 19, 2014.</ref> As these frogs are endangered, their harvest is [[Ethics|unethical]]. Biosynthetic studies are also challenged by the slow rate of synthesis of batrachotoxin.<ref name=":0" />

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

{{|Arrow poison|}}

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.

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.

====

* [[Tetrodotoxin]], a toxin that works in the opposite way of batrachotoxin

== Citations ==

==General and cited references==

* {{cite book |author1=Daly, J. W. |author2=Witkop, B. |year=1971 |chapter=Chemistry and Pharmacology of Frog Venoms |chapter-url=https://archive.org/details/venomousanimalst0002buch/page/496/mode/2up |editor1=Bücherl, W. |editor2=Buckley, E. E. |editor3=Deulofeu, V. |title=Venomous Animals and Their Venoms |url=https://archive.org/details/venomousanimalst0002buch |url-access=registration |volume=2 |location=New York |publisher=Academic Press |lccn=66014892 |oclc=299757}}

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[[Category:Enones]]

[[Category:Ethers]]

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[[Category:Non-protein ion channel toxins]]

[[Category:Oxygen heterocycles]]

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[[Category:Steroidal alkaloids]]

[[Category:Tertiary alcohols]]

[[Category:Amphibian toxins]]

[[Category:Insect toxins]]

[[Category:Heterocyclic compounds with 6 rings]]