katosvanidze18851907’s diary

知恵袋、okwaveで質問した回答したものをコピーして載せるだけのブログ。書いた文章は 自分の財産なので。つまりはこのブログは記録する倉庫の役割り。アクセス数やランキングは付録なので興味はない。物事、この世の深淵、本質、真理とは? 全ては知識と文章能力が解決してくれる 知識を付けて盲点を無くしていけば、。ゴールは現状の外に。 現状の外にゴールを作れば未来の記憶が作られるが、現状の内側にゴールを設定すれば、我々は過去にしばれる、過去 の延長線上を生きることに 過去からの脱するに未来に対してイメージ、臨場感を

ネオスチグミン。VXガス。リジン、フグ毒。知識としての確認。

https://ja.m.wikipedia.org/wiki/ネオスチグミン


編集


朝鮮でボールペンに似せた発射機で針を飛翔させ、針に塗布した臭化ネオスチグミンで対象者を殺害するという暗殺用途にも使用され、10mgで対象者を速やかに殺害する事ができるとする脱北者の証言が報道された[1]が、5mgの注射剤が利用可能であり、半数致死量は0.3mg/kgである[2](例えば、仮に体重が100kgであるとすれば推定半数致死量は30mgである)ため、報道された用量においては現実的な暗殺の手段としては考えにくく、信憑性に乏しい。


剤形

ネオスチグミン(英: neostigmine)は、カルバメート化合物の一つで、コリンエステラーゼ阻害剤である。フィゾスチグミンと並んで、非脱分極性筋弛緩薬の拮抗や、アセチルコリン関連の調節機能の改善に用いられる。


市販の点眼薬にもピント調節機能の改善を目的に、メチル硫酸ネオスチグミンとして含まれていることがある。


https://en.m.wikipedia.org/wiki/Neostigmine


Neostigmine, sold under the brand name Prostigmin among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage.[1][2] It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours.[1]


Common side effects include nausea, increased saliva, crampy abdominal pain, and slow heart rate. More severe side effects include low blood pressure, weakness, and allergic reactions. It is unclear if use in pregnancy is safe for the baby. Neostigmine is in the cholinergic family of medications. It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.[1]


Neostigmine was patented in 1931.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] The wholesale cost in the developing world is about 0.18 to 2.6 USD per dose.[5]The term is from Greek neos, meaning "new," and "-stigmine," in reference to its parent molecule, physostigmine, on which it is based.[6]


https://ru.wikipedia.org/wiki/Неостигмина_метилсульфат


Неостигмина метилсульфат («Прозерин») — ингибитор холинэстеразы. По периферической активности близок к физостигмину и галантамину, центрального действия не оказывает, поскольку плохо проникает через гемато-энцефалический барьер.

Прозерин входит в перечень жизненно необходимых и важнейших лекарственных препаратов.


Передозировка[править | править вики-текст]

При передозировке прозерина или повышенной чувствительности к нему могут возникнуть побочные явления, связанные с перевозбуждением холинорецепторов (холинергический криз): гиперсаливация, миоз, тошнота, усиление перистальтики, понос, частое мочеиспускание, подергивание мышц языка и скелетной мускулатуры, постепенное развитие общей слабости. 


Для снятия побочных явлений уменьшают дозу или прекращают приём препарата, при необходимости водят атропин или другие холинолитические препараты.


https://zh.wikipedia.org/wiki/新斯的明


新斯的明(英语:Neostigmine)是一种拟副交感神经药,其作用机理是作为一种易逆乙酰胆碱酯酶抑制药。



https://ko.wikipedia.org/wiki/네오스티그민


네오스티그민(neostigmine)은 가역 아세틸콜린 분해 억제제의 역할을 하는 부교감 신경양 작용제이다. 1931년 애실만(Aeschlimann)과 라이너(Reinert)가 처음 합성하였다.[1]

의학 목적으로 사용되지만 부작용도 있다. 브롬화 네오스티그민(neostigmine bromide)은 사이안화 칼륨(청산가리) 보다 5배 독성이 강하며 파커 만년필 독침의 주원료이기도 하다.


의학적 이용[편집]

네오스티그민은 중증 근무력증이나 마취통증의 근긴장도를 개선하는데 사용되며, 요폐 환자에게도 적용할 수 있다.


부작용[편집]

이 물질은 두통, 이마통, 시력 저하, 수정체떨림, 각막 주위 충혈, 충혈성 홍채염, 각종 알레르기 반응, 또 드물게는 망막박리 등의 부작용이 있다.[2]

서맥 현상을 일으킬 수 있기 때문에 아트로핀이나 글리코피롤레이트 따위의 부교감 신경 억제제와 함께 사용하는 것이 보통이다.

또, 이 물질이 주사된 직후에는 식욕 부진, 메스꺼움, 구토, 복통, 설사 등의 증상을 유발할 수 있다.[3]


브롬화 네오스티그민 관련 사건[편집]

 이 문단의 내용은 출처가 분명하지 않습니다. 지금 바로 이 문단을 편집하여, 참고하신 문헌이나 신뢰할 수 있는 출처를 각주 등으로 표기해 주세요. 검증되지 않은 내용은 삭제될 수도 있습니다. 내용에 대한 의견이 있으시다면 토론 문서에서 나누어 주세요. (2012년 12월 7일에 문단의 출처가 요청되었습니다.)


브롬화 네오스티그민은 조선민주주의인민공화국의 첩보원들이 암살에 사용한 독약이기도 하다.

1996년 10월 1일 최덕근 블라디보스토크 영사가 네오스티그민 브로마이드 중독으로 사망했다.

2011년 8월 21일 김창환 선교사가 중국 단둥에서 사망했다. 12월 국립과학수사연구원에서 브롬화네오스티그민 중독으로 사망했음이 밝혀졌다.


2011년 8월 22일 10여년간 대북 인권활동을 해온 강호빈 목사가 옌지에서 독침을 맞았으나 사망하지 않았다. 2012년 5월 27일 옌벤에서 교통사고로 사망했다.

2011년 9월 3일 대북삐라를 살포하는 자유북한운동연합 박상학 대표를 네오스티그민브로마이드로 독살하려던 탈북자 안모씨가 현장에서 국정원에 체포되었다. 56세인 안모씨는 1996년 탈북자로 2011년 4월 북한 정찰총국 공작원에 포섭되었다. 가족을 평양에 살 게 해주겠다는 회유를 받았다. 안모씨는 황장엽 비서의 측근인 김덕홍 여광무역 대표의 암살도 시도했다.


김정남 죽인 물질 'VX가스' 혹은 '브롬화네오스티그민' 가능성
기사 등록일 2017. 02. 16
최종 수정일 2017. 02. 16
(サリンガスよりも100倍きつい
VXガスと、

青酸カリよりも5倍以上きつい
臭化ネオスチグミン

マレーシア当局は
フグ毒、リジンの可能性も示唆)

金正男毒殺>「警戒されにくい女性が犯行、武器は隠しやすい毒針」
[ⓒ 中央日報/中央日報日本語版]
2017年02月15日 09時24分
18


頭痛を訴えて
泡を吹くのはVXガスの反応と同じ?

テロで使用、、?


1994年8月頃:オウム真理教が合成に成功。「神通」「神通力」と呼ばれていた。
1994年10月:オウム真理教滝本太郎弁護士に対してサリンに続きVXガスを使用。→滝本太郎弁護士サリン襲撃事件
1994年12月2日:駐車場経営者VX襲撃事件
1994年12月12日:会社員VX殺害事件 1998年現在、記録された中では世界で唯一のVXガスによる死亡事例とされる[2]。
1995年1月4日:オウム真理教被害者の会会長VX襲撃事件
1997年4月29日:化学兵器禁止条約Chemical Weapons Convention、CWC)が発効し、使用のみならず、製造・保有も禁じられた。2015年10月現在、同条約署名済み未批准国はイスラエル、未署名国はエジプト、南スーダン北朝鮮[3]。

VX (IUPAC name O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate) is an extremely toxic substance that has no known uses except in chemical warfare as a nerve agent. It is a tasteless and odorless liquid with an amber-like color. 10 milligrams is sufficient for it to be fatal through skin contact and the LCt50 for inhalation is estimated to be 30–50 mg·min/m3. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687. The production and stockpiling of VX exceeding 100 grams per year per signatory was outlawed by the Chemical Weapons Convention of 1993. The only exception is for "research, medical or pharmaceutical purposes outside a single small-scale facility in aggregate quantities not exceeding 10 kg per year per facility."[3]

The VX nerve agent is the best-known of the V-series of nerve agents and is considered an area denial weapon due to its physical properties. It is far more powerful than sarin, another well known nerve agent toxin, but works in a similar way.

Discovery[edit]

In the 1950s, Ranajit Ghosh, a chemist at the Plant Protection Laboratories of the British firm Imperial Chemical Industries (ICI), was investigating a class of organophosphate compounds (organophosphate esters of substituted aminoethanethiols).[4] Like Gerhard Schrader, an earlier investigator of organophosphates, Ghosh found that they were quite effective pesticides. In 1954, ICI put one of them on the market under the trade name Amiton. It was subsequently withdrawn, as it was too toxic for safe use. The toxicity did not go unnoticed, and samples of it had been sent to the British Armed Forces research facility at Porton Down for evaluation. After the evaluation was complete, several members of this class of compounds became a new group of nerve agents, the V agents. The best-known of these is probably VX, assigned the UK Rainbow Code Purple Possum, with the Russian V-Agent coming a close second (Amiton is largely forgotten as VG). This class of compounds is also sometimes known as Tammelin's esters, after Lars-Erik Tammelin of the Swedish National Defence Research Institute. Tammelin was also conducting research on this class of compounds in 1952, but did not widely publicize his work. The name is a contraction of the words "venomous agent X".[5]

Chemical characteristics[edit]

With its high viscosity and low volatility, VX has the texture and feel of motor oil. This makes it especially dangerous, as it has a high persistence in the environment. It is odorless and tasteless, and can be distributed as a liquid, either pure or as a mixture with a polymer in the form of thickened agent, or as an aerosol.

VX is an acetylcholinesterase inhibitori.e., it works by blocking the function of the enzyme acetylcholinesterase. Normally, when a motor neuron is stimulated, it releases the neurotransmitter acetylcholine into the space between the neuron and an adjacent muscle cell. When this acetylcholine is taken up by the muscle cell, it stimulates muscle contraction. To avoid a state of constant muscle contraction, the acetylcholine is then broken down to non-reactive substances (acetic acidand choline) by the enzyme acetylcholinesterase. VX blocks the action of acetylcholinesterase, resulting in an accumulation of acetylcholine in the space between the neuron and muscle cell, leading to uncontrolled muscle contraction. This results in initial violent contractions, followed by sustained supercontraction restricted to the subjunctional endplatesarcoplasm and prolonged depolarizing neuromuscular blockade, the latter resulting in flaccid paralysis of all the muscles in the body. Sustained paralysis of the diaphragm muscle causes death by asphyxiation.

Synthesis[edit]

VX is produced via the "transester process". This entails a series of steps whereby phosphorus trichloride is methylated to produce methyl phosphonous dichloride. The resulting material is reacted with ethanol to form a diester. This is then transesterified with N,N-diisopropylaminoethanol to produce the mixed phosphonite. Finally, this immediate precursor is reacted with sulfur to form VX.

VX TransesterProcess.png

VX can also be delivered in binary chemical weapons which mix in-flight to form the agent prior to release. Binary VX is referred to as VX2,[6] and is created by mixing O-(2-diisopropylaminoethyl) O′-ethyl methylphosphonite (Agent QL) with elemental sulfur (Agent NE) as is done in the Bigeye aerial chemical bomb. It may also be produced by mixing with sulfur compounds, as with the liquid dimethyl polysulfide mixture (Agent NM) in the canceled XM-768 8-inch binary projectile program.[citation needed]

Solvolysis[edit]

Like other organophosphorus nerve agents, VX may be destroyed by reaction with strong nucleophiles. The reaction of VX with concentrated aqueous sodium hydroxide results in competing cleavage of the P-O and P-S esters, with P-S cleavage dominating. This is somewhat problematic, as the product of P-O bond cleavage (named EA 2192) remains toxic. In contrast, reaction with the hydroperoxide anion (hydroperoxidolysis) leads to exclusive cleavage of the P-S bond.[7][8]

VX-solvolysis-P-S-2D-skeletal.pngP-S cleavage
NaOH(aq) reacts with VX in two ways. It can cleave VX's P-S bond, yielding two relatively nontoxic products...
VX-solvolysis-P-O-2D-skeletal.pngP-O cleavage
...or it can cleave VX's P-O bond, forming ethanol and EA 2192 (shown in red), which has similar toxicity to VX itself

Biological effects[edit]

VX is the most toxic nerve agent ever synthesized for which activity has been independently confirmed.[9] The median lethal dose (LD50) for humans is estimated to be about 10 milligrams[10] through skin contact and the LCt50 for inhalation is estimated to be 30–50 mg·min/m3.[10]

Early symptoms of percutaneous exposure (skin contact) may be local muscular twitching or sweating at the area of exposure followed by nausea or vomiting. Some of the early symptoms of a VX vapor exposure to nerve agent may be rhinorrhea (runny nose) and/or tightness in the chest with shortness of breath (bronchial constriction). Miosis (pinpointing of the pupils) may be an early sign of agent exposure but is not usually used as the only indicator of exposure.[11]

Treatment[edit]

Primary consideration should be given to removal of the liquid agent from the skin before removal of the individual to an uncontaminated area or atmosphere. After removal from the contaminated area, the casualty will be decontaminated by washing the contaminated areas with household bleach and flushing with clean water. After decontamination, the contaminated clothing is removed and skin contamination washed away. If possible, decontamination is completed before the casualty is taken for further medical treatment.

An individual who has received a known nerve-agent exposure or who exhibits definite signs or symptoms of nerve-agent exposure should immediately have the nerve agent antidote drugs atropine and pralidoxime (2-PAM), and a sedative/antiepileptic such as diazepaminjected. In several nations the nerve agent antidotes are issued for military personnel in the form of an autoinjector such as the United States military Mark I NAAK.[11]

Atropine works by binding and blocking a subset of acetylcholine receptors (known as muscarinic acetylcholine receptor, mAchR), so that the buildup of acetylcholine produced by loss of the acetylcholinesterase function has a reduced effect on their target receptor.

VX (and other organophosphates) block the enzymatic activity of acetylcholinesterase (AChE) by binding to the active site of the enzyme. The phosphate group on VX is then transferred from VX to AChE, inactivating the enzyme and producing an inactive metabolite of VX. The injection of pralidoxime (2-PAM) removes the phosphate group from AChE, reactivating it, thereby reversing the effects of VX. If pralidoxime is not given soon enough, the inactivated enzyme will "age", resulting in a much stronger AChEW-phosphate that pralidoxime cannot reverse.[12][13]

Diagnostic tests[edit]

Controlled studies in humans have shown that minimally toxic doses cause 70–75% depression of erythrocyte cholinesterase within several hours of exposure. The serum level of ethyl methylphosphonic acid(EMPA), a VX hydrolysis product, was measured to confirm exposure in one poisoning victim.[14]

History[edit]

Further information: Nerve agent § History

The chemists Ranajit Ghosh La-a and J.F. Newman discovered the V-series nerve agents at ICI in 1952, patenting diethyl S-2-diethylaminoethyl phosphono- thioate (agent VG) in November 1952. Further commercial research on similar compounds ceased in 1955 when its lethality to humans was discovered. The US went into production of large amounts of VX in 1961 at Newport Chemical Depot.

There was evidence of a combination of chemical agents having been used by Iraq against the Kurds at Halabja in 1988 under Saddam Hussein.[15] Hussein later testified to UNSCOM that Iraq had researched VX, but had failed to weaponize the agent due to production failure. After U.S. and allied forces had invaded Iraq, no VX agent or production facilities were found. However, UNSCOM laboratories detected traces of VX on warhead remnants.[16][17]

In December 1994 and January 1995, Masami Tsuchiya of Aum Shinrikyosynthesized 100 to 200 grams of VX which was used to attack three persons. Two persons were injured and one 28-year-old man died, who is believed to be the only fully documented victim of VX ever in the world.[18]The VX victim, whom Shoko Asahara had suspected as a spy, was attacked at 7:00 am on December 12, 1994 on the street in Osaka by Tomomitsu Niimi and another AUM member, who sprinkled the nerve agent on his neck. He chased them for about 100 yards (90 metres) before collapsing, dying 10 days later without ever coming out of a deep coma. Doctors in the hospital suspected at the time he had been poisoned with an organophosphate pesticide, but the cause of death was pinned down only after cult members arrested for the subway attackconfessed to the killing. Ethyl methylphosphonate, methylphosphonic acid and diisopropyl-2-(methylthio) ethylamine were later found in the body of the victim. Unlike the cases for sarin gas (the Matsumoto incident and the attack on the Tokyo subway), VX was not used for mass murder.

Some countries known to possess VX are the United States, Russia,[19]and Syria.[20] A Sudanese pharmaceutical facility, the Al-Shifa pharmaceutical factory, was bombed by the U.S. in 1998 acting on information that it produced VX and that the origin of the agent was associated with both Iraq and Al Qaeda.[16] The US had obtained soil samples identified as containing O-ethyl hydrogen methylphosphonothioate (EMPTA), a chemical used in the production of VX which may also have commercial applications. Chemical weapons experts later suggested that the widely used Fonophos organophosphate insecticide could have been mistaken for EMPTA.[21]

US VX stockpile elimination[edit]

In 1969, the US government canceled its chemical weapons programs, banned the production of VX in the US, and began the destruction of its stockpiles of agents by a variety of methods. Early disposal included the US Army's CHASE (Cut Holes And Sink 'Em) program, in which old ships were filled with chemical weapons stockpiles and then scuttled. CHASE 8 was conducted on June 15, 1967, in which the S.S. Cpl. Eric G. Gibsonwas filled with 7,380 VX rockets and scuttled in 7,200 feet (2,200 m) of water, off the coast of Atlantic City, New Jersey.

In fiscal year 2008, the US Department of Defense released a study finding that the U.S. had dumped at least 124 tons of VX into the Atlantic Ocean off the coasts of New York/New Jersey and Florida, between 1969 and 1970. This material consisted of nearly 22,000 M55 rockets, 19 bulk containers holding 1,400 pounds (640 kg) each, and one M23 chemical landmine.[22]

Incineration was used for VX stockpile destruction starting in 1990 with Johnston Atoll Chemical Agent Disposal System in the North Pacific with other incineration plants following at Deseret Chemical DepotPine Bluff ArsenalUmatilla Chemical Depot and Anniston Army Depot with the last of the VX inventory destroyed on December 24, 2008.[23]

The Newport Chemical Depot began VX stockpile elimination using chemical neutralization in 2005. VX was hydrolyzed to much less toxic byproducts by using concentrated caustic solution, and the resulting waste was then shipped off-site for further processing. Technical and political issues regarding this secondary byproduct resulted in delays, but the depot completed their VX stockpile destruction in August, 2008.[24]

The remaining VX stockpile in the US will be treated by the Blue Grass Chemical Agent-Destruction Pilot Plant, part of the Program Executive Office, Assembled Chemical Weapons Alternatives program. The program was established as an alternative to the incineration process successfully used by the Army Chemical Materials Agency, which completed its stockpile destruction activities in March 2012. The Blue Grass Pilot Plant has been plagued by repeated cost over-runs and schedule slippages since its inception.[25]

Worldwide VX stockpile elimination[edit]

Worldwide, VX disposal has continued since 1997 under the mandate of the Chemical Weapons Convention.

In Russia, the US is providing support for these destruction activities with the Nunn-Lugar Global Cooperation Initiative.[26]  The Initiative has been able to convert a former chemical weapons depot at ShchuchyeKurgan Oblast, into a facility to destroy those chemical weapons. The new facility, which opened in May 2009, has been working on eliminating the nearly 5,950 tons of nerve agents held at the former storage complex. However, this facility only holds about 14% of Russian chemical weapons that are stored throughout[vague] seven sites.[27]

In popular culture[edit]

One of the best-known references to VX in popular culture is its use in the 1996 film The Rock,[28][29] which centers on a threatened VX attack on San Francisco from the island of Alcatraz. The film uses a certain artistic license, notably with VX being ascribed corrosive powers it does not possess, permitting an early scene in which a VX victim is shown with his face melting, rather than dying through asphyxiation. It also shows the hero applying an intracardiac injection of atropine as a defense against VX contamination, rather than the more usual intramuscular injection (e.g. into the thigh) of a combination of atropine and pralidoxime.

In the BBC One spy drama Spooks, an episode named "I Spy Apocalypse" (Series 2, Episode 5) features an EERE (Extreme Emergency Response Exercise) turned real life emergency. A dirty bombwas reported to have exploded in Parliament Square and later the Morningside area of Edinburgh. The bomb was confirmed to have dispersed VX in quantities that exceeded the lethal dose across much of the southeast of England. It is later found that the emergency is a well constructed and believable exercise designed to test the MI5 officers to their limits.

In the CBS American science-based drama television series Eleventh Hour, an episode named Subway (Episode 16); Dr Hood, a science advisor to the FBI is called in to determine the cause of a poison cluster, which is killing people in Philadelphia.[30]

VX agent was featured on the History Channel's television series Modern Marvels in the episode Deadliest Weapons (Season 11, Episode 10).[31]

Another reference to VX is found in the 2012 art-house dark comedy film It's a Disaster. The film centers around four couples that gather for a regular couples brunch and later learn about a multi-city VX attack on the United States that may threaten their lives.[32][33]





リシンlysine)はα-アミノ酸のひとつで側鎖に 4-アミノブチル基を持つ。リジンと表記あるいは音読する場合もある。 タンパク質構成アミノ酸で、必須アミノ酸である。略号は Lys あるいは K である。側鎖にアミノ基を持つことから、塩基性アミノ酸に分類される。リシンは、クエン酸回路に取り込まれてエネルギーを生み出すケト原性アミノ酸である。

栄養学編集

必須アミノ酸であるが、植物性蛋白質における含量が低く、動物性蛋白質摂取量の少ない地域での栄養学上の大きな問題となっている。3大穀物である小麦トウモロコシなど穀類のリシン含有量が少ないので、リシンを豊富に含む副食(乳製品など)を必要とする[1]サプリメントとしてヘルペスの予防にも利用される。

WHOによるリシンの成人向け一日当たり推奨摂取量は2.1グラムである[2]

穀物中には豊富には含まれないが、豆類には豊富である。肉、魚、乳製品にも多く含まれる。多量のリシンを含む植物には以下のようなものがある。

リシンは蛋白質分子に対してメチル化アセチル化による翻訳後修飾を行う。コラーゲンはリシンの誘導体であるヒドロキシリシンを含む。細胞から分泌が行われる際に、小胞体またはゴルジ体におけるリシン残基のO-グリコシル化が特定の蛋白質に印を付けるのに使われる。


生化学

代謝編集

哺乳類においてはα-ケトグルタル酸とのアミノ基転移反応を経てアセチルCoAへと代謝されクエン酸回路に入る。バクテリアにおいては脱炭酸によりカダベリンとなる。


生合成編集

リシンの生合成はアスパラギン酸β-アスパルチルリン酸アスパラギン酸セミアルデヒドジアミノピメリン酸の順に行われる。カビ類においては、α-ジアミノピメリン酸を経由する。


https://hfnet.nih.go.jp/contents/indiv_agreement.html?632

https://ja.wikipedia.org/wiki/リシン_(毒物)

リシン (Ricin) は、トウゴマ(ヒマ)の種子から抽出されるタンパク質である。ヒマの種子に毒性があることは古くから知られていたが、1888年エストニアのスティルマルク (en) が種子から有毒なタンパク質を分離し、リシンと名付けた。

概要[編集]

猛毒であり、人体における推定の最低致死量は体重1kgあたり0.03mg。毒作用は服用の10時間後程度(たんぱく質合成が停止、それが影響していくことによる仕組みのため)。リシン分子はAサブユニットとBサブユニットからなり、Bサブユニットが細胞表面のレセプターに結合してAサブユニットを細胞内に送り込む。Aサブユニットは細胞内のタンパク質合成装置リボゾームの中で重要な機能を果たす28S rRNAの中枢配列を切断する酵素として機能し、タンパク質合成を停止させることで個体の生命維持を困難にする。この作用は腸管出血性大腸菌O157の作るベロ毒素と同じである。吸収率は低く、経口投与より非経口投与の方が毒性は強いが、その場合の致死量はデータなし。戦時中はエアロゾル化したリシンが、化学兵器として使用された事もある。また、たんぱく質としては特殊な形をしているため、胃液膵液などによって消化されず、変性しない。

解毒[編集]

現在、リシンに対して実用化されている解毒剤は存在しない。ただし、米テキサス大学で2004年に開発されたワクチン臨床試験FDAの認可の下に行われ、2006年1月30日付の米国科学アカデミー紀要電子版において予防効果を確認したと報じられている。また、ニュー・サイエンティスト誌では2007年7月4日付で、リシン・コレラ毒素・ベロ毒素の吸収を阻害する分子構造がセントルイス・ワシントン大学医学部の研究により発見されたと報じている[1]

構造[編集]

リシンの立体構造
青 = RTA
緑 = RTB鎖
赤 = 糖側鎖

タンパク質としては、糖鎖を持つ糖タンパク質のひとつ。

RTAの259位のシステインとRTBの4位のシステインの間に形成されるジスルフィド結合により両鎖は結合している。

リシンに関する事件[編集]

1978年9月7日ロンドンブルガリア出身の作家ゲオルギー・マルコフが倒れ、4日後に死亡した。このニュースを聞いて驚いたパリ在住のウラジミール・コストフは何者かに傘の先端で突かれた2週間前の経験から直ちに病院で検査した結果、リシンが封入された約1mmの白金-イリジウム合金の弾丸が発見された(厚着をしていたため体内深くまで弾丸が打ち込まれなかった)。その後マルコフの体内からも同種の弾丸が発見され、被害者2名とも共産政権だったブルガリアからの亡命者であったことから、KGBブルガリア秘密警察 (STB) による犯行と考えられた。リシン入りの弾丸を傘に偽装した空気銃により暗殺を行ったのである。

2003年の11月にワシントンD.C.ホワイトハウス宛の手紙に封入されたリシンが検出された。その手紙はホワイトハウスから離れた郵送物を扱う施設で発見され、大事にはいたらなかった。手紙は細かい粉末状の物質を含んでいて、その後のテストによってリシンと確認された。この情報は、2004年2月3日に予備調査でアメリカ上院ビル・フリスト議員(当時の多数党院内総務)のオフィスの郵送物取扱室で同様の事件が発覚するまで公にされなかった。この事件によっていくつかの上院議員のオフィスが予備措置として閉鎖されたが、健康に被害が及んだという人物は現れていない。

2013年の4月にアメリカバラク・オバマ大統領宛の手紙の中にリシンが混入されているものをシークレットサービスが発見した。10年前の事例同様ホワイトハウス近くの郵便物を仕分ける施設で発見されたため、大統領の手元には届いていない。

2013年の5月にニューヨーク市のマイケル・ブルームバーグ市長(当時)および彼が支援する団体「不法な銃に反対する市長たち(Mayors Against Illegal Guns)」のもとに送られてきた手紙からリシンが検出された。先のオバマ大統領の事件と同一犯として、2013年6月にテキサス州の女性が容疑者として逮捕された。

2015年の11月、別居中の夫の焼酎に、ひまし油の原料となる「トウゴマ」から抽出した猛毒のリシンを混ぜ、殺害しようとしたとして、殺人未遂の疑いで、宇都宮市に住む妻が逮捕された。[9]

https://ja.m.wikipedia.org/wiki/フグ

https://ja.m.wikipedia.org/wiki/テトロドトキシ

テトロドトキシン (tetrodotoxin, TTX) は化学式C11H17N3O8で表され、ビブリオ属シュードモナス属などの一部の真正細菌によって生産されるアルカロイドである。一般にフグとして知られるが、他にアカハライモリツムギハゼヒョウモンダコスベスベマンジュウガニなど幾つかの生物もこの毒をもっている。習慣性がないため鎮痛剤として医療に用いられる。分子量319.27、CAS登録番号 [4368-28-9]。語源はフグ科の学名 (Tetraodontidae) と毒 (toxin) の合成語である。

https://en.wikipedia.org/wiki/Ricin

Ricin (/ˈrsɪn/ reye-sin) is a highly toxic, naturally occurring lectin (a carbohydrate-binding protein) produced in the seeds of the castor oil plantRicinus communis. A dose of purified ricin powder the size of a few grains of table salt can kill an adult human.[1] The median lethal dose (LD50) of ricin is around 22 micrograms per kilogram of body weight if the exposure is from injection or inhalation (1.78 milligram for an average adult). [2] Oral exposure to ricin is far less toxic as some of the poison is inactivated in the stomach. An estimated lethal oral dose in humans is approximately 1 milligram per kilogram.[2]

Biochemistry[edit]

Ricin is classified as a type 2 ribosome-inactivating protein (RIP). Whereas type 1 RIPs are composed of a single protein chain that possesses catalytic activity, type 2 RIPs, also known as holotoxins, are composed of two different protein chains that form a heterodimeric complex. Type 2 RIPs consist of an A chain that is functionally equivalent to a type 1 RIP, covalently connected by a single disulfide bond to a B chain that is catalytically inactive, but serves to mediate transport of the A-B protein complex from the cell surface, via vesicle carriers, to the lumen of the endoplasmic reticulum (ER). Both type 1 and type 2 RIPs are functionally active against ribosomes in vitro; however, only type 2 RIPs display cytotoxicity due to the lectin-like properties of the B chain. In order to display its ribosome-inactivating function, the ricin disulfide bond must be reductively cleaved.[3]

Biosynthesis[edit]

Ricin is synthesized in the endosperm of castor oil plant seeds.[4] The ricin precursor protein is 576 amino acid residues in length and contains a signal peptide (residues 1–35), the ricin A chain (36–302), a linker peptide (303–314), and the ricin B chain (315–576).[5] The N-terminal signal sequence delivers the prepropolypeptide to the endoplasmic reticulum(ER) and then the signal peptide is cleaved off. Within the lumen of the ER the propolypeptide is glycosylated and a protein disulfide isomerasecatalyzes disulfide bond formation between cysteines 294 and 318. The propolypeptide is further glycosylated within the Golgi apparatus and transported to protein storage bodies. The propolypeptide is cleaved within protein bodies by an endopeptidase to produce the mature ricin protein that is composed of a 267 residue A chain and a 262 residue B chain that are covalently linked by a single disulfide bond.[4]

Structure[edit]

The quaternary structure of ricin is a globular, glycosylated heterodimer of approximately 60–65 kDa.[6] Ricin toxin A chain and ricin toxin B chain are of similar molecular weights, approximately 32 kDa and 34 kDa, respectively.

  • Ricin toxic A chain (RTA) is an N-glycoside hydrolase composed of 267 amino acids.[7] It has three structural domains with approximately 50% of the polypeptide arranged into alpha-helices and beta-sheets.[8]The three domains form a pronounced cleft that is the active site of RTA.
  • Ricin toxic B chain (RTB) is a lectin composed of 262 amino acids that is able to bind terminal galactose residues on cell surfaces.[9] RTB forms a bilobal, barbell-like structure lacking alpha-helices or beta-sheets where individual lobes contain three subdomains. At least one of these three subdomains in each homologous lobe possesses a sugar-binding pocket that gives RTB its functional character.

While other plants contain the protein chains found in ricin, both protein chains must be present in order to produce toxic effects. For example, plants that contain only protein chain A, such as barley, are not toxic because without the link to protein chain B, protein chain A cannot enter the cell and do damage to ribosomes.[10]

Entry into the cytoplasm[edit]

Ricin B chain binds complex carbohydrates on the surface of eukaryoticcells containing either terminal N-acetylgalactosamine or beta-1,4-linked galactose residues. In addition, the mannose-type glycans of ricin are able to bind cells that express mannose receptors.[11] RTB has been shown to bind to the cell surface on the order of 106-108 ricin molecules per cell surface.[12]

The profuse binding of ricin to surface membranes allows internalization with all types of membrane invaginations. The holotoxin can be taken up by clathrin-coated pits, as well as by clathrin-independent pathways including caveolae and macropinocytosis.[13][14] Intracellular vesiclesshuttle ricin to endosomes that are delivered to the Golgi apparatus. The active acidification of endosomes is thought to have little effect on the functional properties of ricin. Because ricin is stable over a wide pH range, degradation in endosomes or lysosomes offers little or no protection against ricin.[15] Ricin molecules are thought to follow retrograde transport via early endosomes, the trans-Golgi network, and the Golgi to enter the lumen of the endoplasmic reticulum (ER).[16]

For ricin to function cytotoxically, RTA must be reductively cleaved from RTB in order to release a steric block of the RTA active site. This process is catalysed by the protein PDI (protein disulphide isomerase) that resides in the lumen of the ER.[17][18] Free RTA in the ER lumen then partially unfolds and partially buries into the ER membrane, where it is thought to mimic a misfolded membrane-associated protein.[19] Roles for the ER chaperones GRP94,[20] EDEM[21] and BiP[22] have been proposed prior to the 'dislocation' of RTA from the ER lumen to the cytosol in a manner that utilizes components of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. ERAD normally removes misfolded ER proteins to the cytosol for their destruction by cytosolic proteasomes. Dislocation of RTA requires ER membrane-integral E3 ubiquitin ligasecomplexes,[23] but RTA avoids the ubiquitination that usually occurs with ERAD substrates because of its low content of lysine residues, which are the usual attachment sites for ubiquitin.[24] Thus, RTA avoids the usual fate of dislocated proteins (destruction that is mediated by targeting ubiquitinylated proteins to the cytosolic proteasomes). In the mammalian cell cytosol, RTA then undergoes triage by the cytosolic molecular chaperones Hsc70 and Hsp90 and their co-chaperones, as well as by one subunit (RPT5) of the proteasome itself, that results in its folding to a catalytic conformation,[20][25] which de-purinates ribosomes, thus halting protein synthesis.

Ribosome inactivation[edit]

RTA has rRNA N-glycosylase activity that is responsible for the cleavage of a glycosidic bond within the large rRNA of the 60S subunit of eukaryotic ribosomes.[26] RTA specifically and irreversibly hydrolyses the N-glycosidic bond of the adenine residue at position 4324 (A4324) within the 28S rRNA, but leaves the phosphodiester backbone of the RNA intact.[27] The ricin targets A4324 that is contained in a highly conserved sequence of 12 nucleotides universally found in eukaryotic ribosomes. The sequence, 5’-AGUACGAGAGGA-3’, termed the sarcin-ricin loop, is important in binding elongation factors during protein synthesis.[28] The depurination event rapidly and completely inactivates the ribosome, resulting in toxicity from inhibited protein synthesis. A single RTA molecule in the cytosol is capable of depurinating approximately 1500 ribosomesper minute.

Depurination reaction[edit]

Within the active site of RTA, there exist several invariant amino acid residues involved in the depurination of ribosomal RNA.[15] Although the exact mechanism of the event is unknown, key amino acid residues identified include tyrosine at positions 80 and 123, glutamic acid at position 177, and arginine at position 180. In particular, Arg180 and Glu177 have been shown to be involved in the catalytic mechanism, and not substrate binding, with enzyme kinetic studies involving RTA mutants. The model proposed by Mozingo and Robertus,[8] based on X-ray structures, is as follows:

  1. Sarcin-ricin loop substrate binds RTA active site with target adenine stacking against tyr80 and tyr123.
  2. Arg180 is positioned such that it can protonate N-3 of adenine and break the bond between N-9 of the adenine ring and C-1’ of the ribose.
  3. Bond cleavage results in an oxycarbonium ion on the ribose, stabilized by Glu177.
  4. N-3 protonation of adenine by Arg180 allows deprotonation of a nearby water molecule.
  5. Resulting hydroxyl attacks ribose carbonium ion.
  6. Depurination of adenine results in a neutral ribose on an intact phosphodiester RNA backbone.

Toxicity[edit]

Castor beans

Ricin is very poisonous if inhaledinjected, or ingested. It can also be poisonous if dust contacts the eyes or if it is absorbed through damaged skin. It acts as a toxin by inhibiting protein synthesis.[29][30] It prevents cells from assembling various amino acids into proteins according to the messages it receives from messenger RNA in a process conducted by the cell's ribosome (the protein-making machinery)—that is, the most basic level of cell metabolism, essential to all living cells and thus to life itself. Ricin is resistant, but not impervious, to digestion by peptidases. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract, where it may cause mucosal injuries. With appropriate treatment, most patients will make a full recovery.[31][32]

Because the symptoms are caused by failure to make protein, they may take anywhere from hours to days to appear, depending on the route of exposure and the dose. When ingested, gastrointestinal symptoms can manifest within 6 hours; these symptoms do not always become apparent. Within 2 to 5 days of exposure to ricin, effects of ricin on the central nervous systemadrenal glandskidneys, and liver appear.[30]

Ingestion of ricin causes pain, inflammation, and hemorrhage in the mucous membranes of the gastrointestinal system. Gastrointestinal symptoms quickly progress to severe nausea, vomiting, diarrhea, and difficulty swallowing (dysphagia). Hemorrhage causes bloody feces (melena) and vomiting blood (hematemesis). The low blood volume (hypovolemia) caused by gastrointestinal fluid loss can lead to organ failure in the pancreas, kidney, liver, and GI tract and progress to shock. Shock and organ failure are indicated by disorientation, stupor, weakness, drowsiness, excessive thirst (polydipsia), low urine production (oliguria), and bloody urine (hematuria).[30]

Symptoms of ricin inhalation are different from those caused by ingestion. Early symptoms include a cough and fever.[30]

When skin or inhalation exposure occur, ricin can cause an allergy to develop. This is indicated by edema of the eyes and lips; asthma; bronchial irritation; dry, sore throat; congestion; skin redness (erythema); skin blisters (vesication); wheezing; itchy, watery eyes; chest tightness; and skin irritation.[30]

An antidote has been developed by the UK military, although it has not yet been tested on humans.[33][34] Another antidote developed by the U.S. military has been shown to be safe and effective in lab mice injected with antibody-rich blood mixed with ricin, and has had some human testing.[35]

Symptomatic and supportive treatments are available for ricin poisoning, but there is no antidote for ricin available for humans. Existing treatments emphasize minimizing the effects of the poison. Possible treatments include intravenous fluids or electrolytes, airway managementassisted ventilation, or giving medications to remedy seizures and low blood pressure. If the ricin has been ingested recently, the stomach can be flushed by ingesting activated charcoal or by performing gastric lavage. Survivors often develop long-term organ damage. Ricin causes severe diarrhea and vomiting, and victims can die of circulatory shock or organ failure; inhaled ricin can cause fatal pulmonary edema or respiratory failure. Death typically occurs within 3–5 days of exposure.[30]

Although there is no antidote currently available for ricin poisoning, vaccination is possible by injecting an inactive form of protein chain A.[10]This vaccination is effective for several months due to the body's production of antibodies to the foreign protein. In 1978 Bulgarian defector Vladimir Kostov survived a ricin attack similar to the one on Georgi Markov, probably due to his body's production of antibodies. When a ricin-laced pellet was removed from the small of his back it was found that some of the original wax coating was still attached. For this reason only small amounts of ricin had leaked out of the pellet, producing some symptoms but allowing his body to develop immunity to further poisoning.[10]

The seeds of Ricinus communis are commonly crushed to extract castor oil. As ricin is not oil-soluble, little is found in the extracted castor oil.[10]The extracted oil is also heated to more than 80 °C to denature any ricin that may be present.[10] The remaining spent crushed seeds, called variously the "cake", "oil cake", and "press cake", can contain up to 5% ricin.[36] While the oil cake from coconut, peanuts, and sometimes cotton seeds can be used as either cattle feed and/or fertilizer, the toxic nature of castor beans precludes their oil cake from being used as feed unless the ricin is first deactivated by autoclaving.[37] Accidental ingestion of Ricinus communis cake intended for fertilizer has been reported to be responsible for fatal ricin poisoning in animals.[29][38]

Deaths from ingesting castor plant seeds are rare, partly because of their indigestible seed coat, and because the body can, although only with difficulty, digest ricin.[6] The pulp from eight beans is considered dangerous to an adult.[39] Rauber and Heard have written that close examination of early 20th century case reports indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management".[40]

Overdose[edit]

Most acute poisoning episodes in humans are the result of oral ingestion of castor beans, 5–20 of which could prove fatal to an adult. However, swallowing castor beans rarely proves to be fatal unless the bean is thoroughly chewed. The survival rate of castor bean ingestion is 98%.[10]In 2013 a 37-year-old female in the United States survived after ingesting 30 beans.[41] Victims often manifest nauseadiarrheafast heart ratelow blood pressure, and seizures persisting for up to a week.[29] Blood, plasma, or urine ricin or ricinine concentrations may be measured to confirm diagnosis. The laboratory testing usually involves immunoassay or liquid chromatography-mass spectrometry.[42]

Therapeutic applications[edit]

Although no approved therapeutics are currently based on ricin, it does have the potential to be used in the treatment of tumors, as a "magic bullet" to destroy targeted cells.[15] Because ricin is a protein, it can be linked to a monoclonal antibody to target cancerous cells recognized by the antibody. The major problem with ricin is that its native internalization sequences are distributed throughout the protein. If any of these native internalization sequences are present in a therapeutic agent, the drug will be internalized by, and kill, untargeted non-tumorous cells as well as targeted cancerous cells.

Modifying ricin may sufficiently lessen the likelihood that the ricin component of these immunotoxins will cause the wrong cells to internalize it, while still retaining its cell-killing activity when it is internalized by the targeted cells. However, bacterial toxins, such as diphtheria toxin, which is used in denileukin diftitox, an FDA-approved treatment for leukemia and lymphoma, have proven to be more practical. A promising approach for ricin is to use the non-toxic B subunit (a lectin) as a vehicle for delivering antigens into cells, thus greatly increasing their immunogenicity. Use of ricin as an adjuvant has potential implications for developing mucosal vaccines.

Regulation[edit]

In the U.S., ricin appears on the select agents list of the Department of Health and Human Services,[43] and scientists must register with HHS to use ricin in their research. However, investigators possessing less than 100 mg are exempt from regulation.[44]

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[45]

Chemical or biological warfare agent[edit]

A metal vial containing ricin from the 2003 ricin letters

The United States investigated ricin for its military potential during World War I.[46] At that time it was being considered for use either as a toxic dust or as a coating for bullets and shrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the Hague Convention of 1899 (adopted in U.S. law at 32 Stat. 1903), specifically Annex §2, Ch.1, Article 23, stating "... it is especially prohibited ... [t]o employ poison or poisoned arms".[47]World War I ended before the United States weaponized ricin.

During World War II the United States and Canada undertook studying ricin in cluster bombs.[48] Though there were plans for mass productionand several field trials with different bomblet concepts, the end conclusion was that it was no more economical than using phosgene. This conclusion was based on comparison of the final weapons, rather than ricin's toxicity (LCt50 ~40 mg·min/m3). Ricin was given the military symbolW or later WA.[citation needed] Interest in it continued for a short period after World War II, but soon subsided when the U.S. Army Chemical Corpsbegan a program to weaponize sarin.

The Soviet Union also possessed weaponized ricin. There were speculations that the KGB used it outside the Soviet bloc; however, this was never proven.

Given ricin's extreme toxicity and utility as an agent of chemical/biological warfare, it is noteworthy that the production of the toxin is rather difficult to limit. The castor bean plant from which ricin is derived is a common ornamental and can be grown at home without any special care.

Under both the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, ricin is listed as a schedule 1 controlled substance. Despite this, more than 1 million tonnes of castor beans are processed each year, and approximately 5% of the total is rendered into a waste containing negligible concentrations of undenatured ricin toxin.[49]

Ricin is several orders of magnitude less toxic than botulinum or tetanus toxin, but the latter are harder to come by. Compared to botulinum or anthrax as biological weapons or chemical weapons, the quantity of ricin required to achieve LD50 over a large geographic area is significantly more than an agent such as anthrax (tons of ricin vs. only kilogram quantities of anthrax).[50] Ricin is easy to produce, but is not as practical or likely to cause as many casualties as other agents.[31] Ricin is easily denatured by temperatures over 80 °C (175 °F) meaning many methods of deploying ricin would generate enough heat to denature it.[36] Once deployed an area contaminated with ricin remains dangerous until the bonds between chain A or B have been broken, a process that takes two or three days.[10] In contrast, anthrax spores may remain lethal for decades. Jan van Aken, a German expert on biological weapons, explained in a report for The Sunshine Project that Al Qaeda's experiments with ricin suggest their inability to produce botulinum or anthrax.[51]

Developments[edit]

A biopharmaceutical company called Soligenix, Inc. has licensed an anti-ricin vaccine called RiVax™ from Vitetta et al. at UT Southwestern. The vaccine is safe and immunogenic in mice, rabbits, and humans. It has completed two successful clinical trials.[52]

Incidents[edit]

Ricin has been involved in a number of incidents. In 1978, the Bulgariandissident Georgi Markov was assassinated by Bulgarian secret policewho surreptitiously shot him on a London street with a modified umbrellausing compressed gas to fire a tiny pellet contaminated with ricin into his leg.[31][53] He died in a hospital a few days later and his body was passed to a special poison branch of the British Ministry of Defence (MOD) that discovered the pellet during an autopsy. The prime suspects were the Bulgarian secret police: Georgi Markov had defected from Bulgaria some years previously and had subsequently written books and made radio broadcasts that were highly critical of the Bulgarian communist regime. However, it was believed at the time that Bulgaria would not have been able to produce the pellet, and it was also believed that the KGB had supplied it. The KGB denied any involvement, although high-profile KGB defectors Oleg Kalugin and Oleg Gordievsky have since confirmed the KGB's involvement. Earlier, Soviet dissident Aleksandr Solzhenitsyn also suffered (but survived) ricin-like symptoms after an encounter in 1971 with KGB agents.[54]

Ten days before the attack on Georgi Markov, Bulgarian defector, Vladimir Kostov survived an attack similar to the one against Markov. Kostov was standing on an escalator of the Paris metro when he felt a sting in his lower back above the belt of his trousers. He developed a fever, but recovered. After Markov's death the wound on Kostov's back was examined and a ricin-laced pellet identical to the one used against Markov was removed.[10]

Several terrorists and terrorist groups have experimented with ricin and caused several incidents of the poisons being mailed to U.S. politicians. For example, on May 29, 2013 two anonymous letters sent to New York City Mayor Michael Bloomberg contained traces of it.[55] Another was sent to the offices of Mayors Against Illegal Guns in Washington DC. A letter containing ricin was also alleged to have been sent to American PresidentBarack Obama at the same time. An actress, Shannon Richardson, was later charged with the crime, to which she pleaded guilty that December.[56] On July 16, 2014, Richardson was sentenced to 18 years in prison plus a restitution fine of $367,000.[57]

In popular culture[edit]

Ricin has often been used as a plot device, such as in the television series Breaking Bad (Season 2Season 4 and Season 5).[58]

The popularity of Breaking Bad inspired several real-life criminal cases involving ricin or similar substances. Kuntal Patel from London attempted to poison her "controlling and selfish" mother with abrin after the latter interfered with her marriage plans.[59] Daniel Milzman, a 19-year-old former Georgetown University student, was charged with manufacturing ricin in his dorm room, as well as the intent of "[using] the ricin on another undergraduate student with whom he had a relationship".[60] Mohammed Ali from Liverpool, England was convicted after attempting to purchase 500 mg of Ricin over the dark web from an undercover FBI agent. He was sentenced, on 18 September 2015, to 8 years' imprisonment.[61]


類縁体

同属の類縁体は、下記7種が知られている。

分析方法


編集

毒成分の分析にはHPLC-蛍光検出法やLC-MSまたはLC-MS/MS法を用いる。

毒性編集

  • マウス経口 LD50 0.01 mg/kg
  • マウス皮下 LD50 0.0085 mg/kg

テトロドトキシンは300 ℃以上に加熱しても、分解されないので注意が必要である。ヒトの経口摂取による致死量は1–2mgで、経口摂取では青酸カリの850倍程度の毒性を持つ。


全合成編集

1972年岸義人名古屋大学、当時)が、D,L-テトロドトキシンラセミ体)の全合成に成功した[10][11][12]。2003年には磯部稔西川俊夫[13][14][15]名古屋大学)らと J. Du Bois[16]スタンフォード大学)が別々に初の不斉全合成を達成している。磯部らの全合成はディールス・アルダー反応を鍵反応としており、Du BoisらはC-H結合活性化を用いている。

生物がもつ毒

生物がもつ毒編集

テトロドトキシントラフグクサフグに代表されるフグ毒の成分で、もともと細菌が生産したものが、餌となるヒトデ類、貝類を通して生物濃縮され体内に蓄積されたものと考えられている。 フグやイモリなどの保有生物はTTXに対し高い耐性を持っているため、保有生物自身が中毒死することはない。これは自然に蓄積する濃度のTTXに耐えられるという意味で、作用点となるイオンチャネルの形が他の動物と違うのである。しかし人為的に高濃度のTTXを与えれば中毒する。


フグ毒と毒化に関する研究編集

季節により毒の量が変わり、種によって毒化する部位が異なる。餌の種類を変えて養殖すると、同じ種であってもフグ毒が少なかったり、全くない場合がある[17]

無毒の養殖フグの群れの中に、毒を持つ天然種を放流すると無毒の群れも毒性を帯びることもある。TTX生産菌のVibrio alginolyticus英語版クサフグの消化管内に生息しているが、腸内細菌の一つとして生息している可能性がある[18]。フグは、TTXを含む餌を好んで摂食していることから、フェロモン的な作用も持っているとも考えられる[19]。TTX耐性の低い種は積極的にTTXを排出している[17]

石川県名産の河豚の卵巣の糠漬けの毒素分解の仕組みは未だ不明である[20]。フグ卵巣糠漬では、食用可能な状態にまで減毒している理由として、古くから塩漬・糠漬中に卵巣から毒が桶に拡散するためと説明されているものの、何がどのように作用するかの解明には至っていない。糠漬け1年後には総毒量が10分の1ほどに減少しており、東京海洋大学微生物の関与を調査したが、微生物のフグ毒の毒力減少への関与は認められていない[21]。 フグ毒については未だ解明されていない部分が多いのが実情である[22][23][24]

耐性編集

幾つかの生物では、耐性の仕組みが解明されつつある[25]

フグ以外の主な保有生物編集


ここに記載されている生物全てが常にTTXを蓄積している訳ではなく[26]、生息域や季節で保有の有無や毒の量は変化する。

  • フグ:マフグなど皮膚から分泌する種が知られ、また多くの魚食性の魚類が味覚でテトロドトキシンを感じて忌避していることから捕食者の回避、また卵巣に蓄積する種が多いことから、卵を捕食されることを防ぐ意義があると考える説がある。また、フェロモン的な作用で産卵期にメスがオスを誘引する[19]
  • ヒョウモンダコ:餌のカニなどを捕獲する際に、顎板でかみついてから毒素を唾液腺から分泌して体内に注入し、獲物を麻痺させている。
  • カリフォルニアイモリ:皮膚からの分泌を行い、捕食者の回避を行っているとされる。

中毒

外傷性中毒編集

ヒョウモンダコによる咬傷 


毒化した魚介類の有毒部位の摂食により発症する。家庭での素人料理が原因になることが多い。従って、中毒を防止するために食品衛生法により都道府県知事等が認めた者及び施設に限って取り扱うこととされている。フグ#流通に関わる関連法規 も参照。


臨床所見

神経毒であるテトロドトキシン神経細胞筋線維細胞膜に存在する電位依存性ナトリウムチャネルを抑制することで、活動電位の発生と伝導を抑制する。そのため、フグ毒の摂取による主な症状は麻痺である。

症状編集

摂食後の20分程度から数時間で症状が現れる。意識が明瞭なまま麻痺は急速に進行し24時間以内に死亡する場合が多い。

第1段階
指先や口唇部および舌端に軽い痺れ。目眩により歩行困難。頭痛や腹痛の場合も有り。
第2段階
運動麻痺が進行、嘔吐、知覚麻痺、言語障害、呼吸困難、血圧降下。
第3段階
全身の麻痺症状、骨格筋の弛緩、呼吸困難及び血圧降下が進行。
第4段階
意識の消失、呼吸停止。死亡。(但し、呼吸停止後も暫くは心臓の拍動が続くことがある)


処置方法編集

拮抗薬や特異療法が存在しない為、2012年現在、解毒方法は見つかっていない。アコニチンなど逆にナトリウムチャネルを活性化する化合物はテトロドトキシンの作用を抑制するが、それ自身も毒であるため、いずれにせよ死に至る。テトロドトキシンは、臨床所見の項にもあるように、神経伝達を遮断して麻痺を起こす。このため、脳からの呼吸に関する指令が遮られ、呼吸器系の障害が起き、それが死につながるのである。しかし、素早く人工呼吸などの適切な処置がなされれば救命率は高いとされる。体内に吸収されたテトロドトキシンは、人体内で代謝によって分解されて無毒化されて排出される。テトロドトキシンは、神経自体を破壊しているわけではないので、排出さえされれば神経伝達が再開するからである。平たく言えば、麻痺症状が現れたときに間髪入れずに人工呼吸を施し、テトロドトキシンが無毒化排出されて、神経伝達の遮断(麻痺)がなくなるまで人工呼吸を続ければよいのである。しかし現実には、麻痺が出たときに間髪入れずに人工呼吸をすることが非常に難しい[31]


神経保護作用

シアン化ナトリウムの神経毒に対し、テトロドトキシンは 1 µM 濃度以上で神経保護が発現する。ベラトリジンの神経毒に対するテトロドトキシの神経保護作用は IC50=30 nM [32]



https://en.wikipedia.org/wiki/Tetrodotoxin

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfishporcupinefishocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other aquatic animals (e.g., in blue-ringed octopusesrough-skinned newts, and moon snails), it is actually produced by certain infecting or symbiotic bacteria like PseudoalteromonasPseudomonas, and Vibrioas well as other species found in the animals[citation needed].

Tetrodotoxin inhibits the firing of action potentials in nerves by binding to the voltage-gated sodium channels in nerve cellmembranes and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the nerve cell (in layman terms, it prevents the nervous system from carrying messages and prevents muscles from flexing).[1]

Its mechanism of action, selective blocking of the sodium channel, was shown definitively in 1964 by Toshio Narahashi and John W. Moore at Duke University, using the sucrose gap voltage clamp technique.[2]


Sources in nature[edit]

Apart from their bacterial species of most likely ultimate biosynthetic origin (see below), tetrodotoxin has been isolated from widely differing animal species, including:[3]

Tarichatoxin was shown to be identical to TTX in 1964 by Mosher et al,[9][10] and the identity of maculotoxin and TTX was reported in Sciencein 1978,[11] and the synonymity of these two toxins is supported in modern reports (e.g., at Pubchem[12] and in modern toxicology textbooks[13]) though historic monographs questioning this continue in reprint.[14]

The toxin is variously used by metazoans as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (e.g., in octopuses, chaetognaths, and ribbon worms).[citation needed] Even though the toxin acts as a defense mechanism, some predators such as the common garter snake have developed insensitivity to TTX, which allows them to prey upon toxic newts.[15]

The association of TTX with consumed, infecting, or symbiotic bacterial populations within the metazoan species from which it is isolated is, as of 2016, relatively clear;[3] presence of TTX-producing bacteria within a metazoan's microbiome is determined by culture methods, the presence of the toxin by chemical analysis, and the association of the bacteria with TTX production by toxicity assay of media in which suspected bacteria are grown.[4] As Lago et al. note, "there is good evidence that uptake of bacteria producing TTX is an important element of TTX toxicity in marine metazoans that present this toxin."[4] TTX-producing bacteria include ActinomycesAeromonasAlteromonasBacillusPseudomonas, and Vibrio species;[4] in the following animals, specific bacterial species have been implicated:[3]

  • Vibrio species including Vibrio alginolyticus, from the puffer fish, Fugu vermicularis,[1][3][4][16]
  • Vibrio alginolyticus, from the starfish species Astropecten polyanthus,[1][4]
  • Aeromonas species from the puffer fishTakifugu obscures,[1][4]
  • both Vibrio, Pseudomonas, and Aeromonas species from gastropod Niotha clathrata,[1][3][4]
  • Alteromonas, Bacillus, Pseudomonas, and Vibrio species from the blue-ringed octopus species Hapalochlaena macula,[1][3][4][17]
  • Vibrio species, including Vibrio alginolyticus again, in arrow worms, phylum Chaetognatha,[3][18] and
  • Vibrio species, again, in ribbon worms, phylum Nemertea.[3][19]

The association of bacterial species with the production of the toxin is unequivocal—Lago and coworkers state, "[e]ndocellular symbiotic bacteria have been proposed as a possible source of eukaryotic TTX by means of an exogenous pathway,"[4] and Chau and coworkers note that the "widespread occurrence of TTX in phylogenetically distinct organisms… strongly suggests that symbiotic bacteria play a role in TTX biosynthesis"[3]—although the correlation has been extended to most but not all metazoans in which the toxin has been identified.[1][3][4] To the contrary, there has been a failure in a single case, that of newts (Taricha granulosa), to detect TTX-producing bacteria in the tissues with highest toxin levels (skin, ovaries, muscle), using PCR methods, although technical concerns about the approach have been raised.[3] Critically for the general argument, Takifugu rubripes puffers captured and raised in laboratory on controlled, TTX-free diets "lose toxicity over time," while cultured, TTX-free Fugu niphobles puffers fed on TTX-containing diets saw TTX in the livers of the fishes increase to toxic levels.[3] Hence, as bacterial species that produce TTX are broadly present in aquatic sediments, a strong case is made for ingestion of TTX and/or TTX-producing bacteria, with accumulation and possible subsequent colonization and production.[3] Nevertheless, without clear biosynthetic pathways (not yet found in metazoans, but shown for bacteria),[20] it remains uncertain whether it is simply via bacteria that each metazoan accumulates TTX; whether the quantities can be sufficiently explained by ingestion, this plus colonization, or some other mechanism.[1][3][4]

Biochemistry[edit]

Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel.[21] Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel, thereby blocking the passage of sodium ions into the nerve cell (which is ultimately necessary for nerve conduction); neosaxitoxin and several of the conotoxins also bind the same site.

The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+channel). Tetrodotoxin binds to TTX-s Na+ channels with a binding affinity of 5–15 nM, while the TTX-r Na+ channels bind TTX with low micromolaraffinity.[22][not in citation given] Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+channels dominate the rest of the body.

TTX and its analogs have historically been important agents for use as chemical tool compounds, for use in channel characterization and in fundamental studies of channel function.[23][24] The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.

Chemical synthesis[edit]

In 1964 a team of scientists led by Robert B. Woodward at Harvard University elucidated the structure of tetrodotoxin.[25] The structure was confirmed by X-ray crystallography in 1970.[26] Yoshito Kishi and coworkers at Nagoya UniversityNagoyaJapan, (now at Harvard University) reported the first total synthesis of D,L-tetrodotoxin in 1972.[27][28] M. Isobe and coworkers at Nagoya University, Japan[29][30][31]and J. Du Bois et al. at Stanford University, U.S., reported the asymmetrictotal synthesis of tetrodotoxin in 2003.[32] The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C-H bond activation. Since then, methods have rapidly advanced, with several new strategies for the synthesis of tetrodotoxin having been developed.[33][34]

Poisoning[edit]

Toxicity[edit]

TTX is extremely toxic. The Material Safety Data Sheet for TTX lists the oral median lethal dose (LD50) for mice as 334 μg per kg.[35] For comparison, the oral LD50 of potassium cyanide for mice is 8.5 mg per kg,[36] demonstrating that even orally, TTX is more poisonous than cyanide. TTX is even more dangerous if injected; the amount needed to reach a lethal dose by injection is only 8 μg per kg in mice.[37]

The toxin can enter the body of a victim by ingestion, injection, or inhalation, or through abraded skin.[38]

Poisoning occurring as a consequence of consumption of fish from the order Tetraodontiformes is extremely serious. The organs (e.g. liver) of the pufferfish can contain levels of tetrodotoxin sufficient to produce the described paralysis of the diaphragm and corresponding death due to respiratory failure.[39] Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic.[1]

The mechanism of toxicity is through the blockage of fast voltage-gated sodium channels, which are required for the normal transmission of signals between the body and brain.[40] As a result, TTX causes loss of sensation, and paralysis of voluntary muscles including the diaphragm and intercostal muscles, stopping breathing.[41]

History[edit]

A Chinese Pharmacopoeia

The therapeutic uses of puffer fish (tetraodon) eggs were mentioned in the first Chinese pharmacopea (Pen-T’ so Ching, The Book of Herbs, allegedly 2838–2698 BC by Shénnóng Běn Cǎo Jīng; but a later date is more likely), where they were classified as having ‘medium’ toxicity, but could have a tonic effect when used at the correct dose. The principle use was “to arrest convulsive diseases”.[42] In the Pen-T’ so Kang Mu (Index Herbacea or The Great Herbal by Li Shih-Chen, 1596) some types of the fish Ho-Tun (the current Chinese name for tetraodon) were also recognized as both toxic and (at the right dose) could be used to prepare a tonic. Increased toxicity in Ho-Tun was noted in fish caught at sea (rather than river) after the month of March. It was recognized that the most poisonous parts were the liver and eggs, but that toxicity could be reduced by soaking the eggs,[42] noting that tetrodotoxin is slightly water-soluble, and soluble at 1 mg/mL in slightly acidic solutions.[43]

The German physician Engelbert Kaempfer, in his "A History of Japan" (translated and published in English in 1727), described how well known the toxic effects of the fish were, to the extent that it would be used for suicide and that the Emperor specifically decreed that soldiers were not permitted to eat it. There is also evidence from other sources that knowledge of such toxicity was widespread throughout southeast Asia and India.[42]

The first recorded cases of TTX poisoning affecting Westerners are from the logs of Captain James Cook from 7 September 1774.[39] On that date Cook recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew survived a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus being fatally poisoned.

The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara.[39] It was one of the agents studied by Japan's Unit 731, which evaluated biological weapons on human subjects in the 1930s.[44]

Symptoms and treatment[edit]

The diagnosis of pufferfish poisoning is based on the observed symptomatology and recent dietary history.[45]

Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, if the dose is fatal, symptoms are usually present within 17 minutes of ingestion.[39] Paresthesia of the lips and tongue is followed by developing paresthesia in the extremities, hypersalivation, sweating, headache, weakness, lethargy, incoordination, tremor, paralysis, cyanosisaphoniadysphagia, and seizures. The gastrointestinal symptoms are often severe and include nausea, vomiting, diarrhea, and abdominal pain; death is usually secondary to respiratory failure.[41][45] There is increasing respiratory distress, speech is affected, and the victim usually exhibits dyspneacyanosismydriasis, and hypotension. Paralysis increases, and convulsions, mental impairment, and cardiac arrhythmia may occur. The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death, which generally occurs within 4 to 6 hours (range ~20 minutes to ~8 hours). However, some victims enter a coma.[41][46]

If the patient survives 24 hours, recovery without any residual effects will usually occur over a few days.[45]

Therapy is supportive and based on symptoms, with aggressive early airway management.[39] If ingested, treatment can consist of emptying the stomach, feeding the victim activated charcoal to bind the toxin, and taking standard life-support measures to keep the victim alive until the effect of the poison has worn off.[39] Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension; anticholinesterase agents "have been proposed as a treatment option but have not been tested adequately".[46]

No antidote has been developed and approved for human use, but a primary research report (preliminary result) indicates that a monoclonal antibody specific to tetrodotoxin is in development by USAMRIID that was effective, in the one study, for reducing toxin lethality in tests on mice.[47]

Geographic frequency of toxicity[edit]

Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions, but pufferfishes from other regions are much less commonly eaten. Several reported cases of poisonings, including fatalities, involved pufferfish from the Atlantic OceanGulf of Mexico, and Gulf of California. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus, but in three studies, extracts from fish of this species were highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin, which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish, and at least one report of a fatal episode in Oregon when an individual swallowed a rough-skinned newt Taricha granulosa.[48]

In 2009, a major scare in the Auckland Region of New Zealand was sparked after several dogs died eating Pleurobranchaea maculata (grey side-gilled seaslug) on beaches.[49] Children and pet owners were asked to avoid beaches, and recreational fishing was also interrupted for a time. After exhaustive analysis, it was found that the sea slugs must have ingested tetrodotoxin.[50]

Statistical factors

Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of fugu poisoning per year between 1996 and 2006 in the entire country, leading to 34–64 hospitalizations and 0–6 deaths per year, for an average fatality rate of 6.8%.[51] Of the 23 incidents recorded within Tokyo between 1993 and 2006, only one took place in a restaurant, while the others all involved fishermen eating their catch.[51] From 2006 through 2009 in Japan there were 119 incidents involving 183 people but only 7 people died.[52]

Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare.[citation needed] In Haiti, tetrodotoxin is thought to have been used in voodoo preparations, in so-called zombie poisons, where subsequent careful analysis has repeatedly called early studies into question on technical grounds, and have failed to identify the toxin in any preparation,[53][54][55] such that discussion of the matter has all but disappeared from the primary literature since the early 1990s. Kao and Yasumoto concluded in the first of their papers in 1986 that "the widely circulated claim in the lay press to the effect that tetrodotoxin is the causal agent in the initial zombification process is without factual foundation.”[53]:748

Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans.

Fugu as a food

Poisoning from tetrodotoxin is of particular public health concern in Japan, where pufferfish "fugu" is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove the viscera to reduce the danger of poisoning.[56] There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.

Food analysis[edit]

The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry.

Detection in body fluids[edit]

Tetrodotoxin may be quantified in serum, whole blood or urine to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a case of fatal overdosage. Most analytical techniques involve mass spectrometric detection following gas or liquid chromatographic separation.[57]

Modern therapeutic research[edit]

Tetrodotoxin has been investigated as a possible treatment for cancer-associated pain. Early clinical trials demonstrate significant pain relief in some patients.[58][59]

In addition to the cancer pain application mentioned, mutations in one particular TTX-sensitive Na+ channel are associated with some migraineheadaches,[60] although it is unclear as to whether this has any therapeutic relevance for most people with migraine.[61]

Tetrodotoxin has been used clinically to relieve the headache associated with heroin withdrawal.[62]

Regulation[edit]

In the U.S., tetrodotoxin appears on the select agents list of the Department of Health and Human Services,[63] and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 500 mg are exempt from regulation.[64]

Popular culture[edit]

Tetrodotoxin serves as a plot device for characters to fake death, as in the films Miami Vice (1985),[65] Hello Again (1987), The A-Team (2010) and Captain America: The Winter Soldier (2014), and in episodes of NikitaMacGyver Season 7, Episode 6, where the antidote is datura stramonium leafCSI: NY (Season 4, episode 9 "Boo") and Chuck. In Law Abiding Citizen (2009) its paralysis is presented as a method of assisting torture. The toxin is used as a weapon in Covert Affairs.[66][67] In episode 16 of Dragon Ball, the characters are inadvertently poisoned by a puffer fish soup. In season 2 episode 11 of The Simpsons, Homer ingests an improperly cut Fugu and is given 22 hours to live.

In the sci-fi series Orphan Black, a half organic, half mechanical "maggot bot" engineered by Evie Cho as a vector for gene therapy delivery to patients, makes use of tetrodotoxin as a defence mechanism to protect the device against tampering.

Based on the presumption that tetrodotoxin is not always fatal, but at near-lethal doses can leave a person extremely unwell with the person remaining conscious,[45] tetrodotoxin has been alleged to result in zombieism, and has been suggested as an ingredient in Haitian Vodoupreparations.[68] This idea first appeared in the 1938 non-fiction book Tell My Horse by Zora Neale Hurston in which there were multiple accounts of purported tetrodotoxin poisoning in Haiti by a voodoo sorcerer called the Bokor.[69] These stories were later popularized by Harvard-trained ethnobotanist Wade Davis[68] in his 1985 book[70] and Wes Craven's 1988 film, both titled The Serpent And The Rainbow. But this theory has been dismissed by the scientific community since the 1990s based on analytical chemistry-based tests of multiple preparations and review of earlier reports (see above).[53][54][55]

In the 2007 remake of The Wizard of Gore, a mind control drug, referred to as Tetrodotoxin, is used by Montag the Magnificent during his performances in order to create his gory illusions.