| Ricin | |||||||
|---|---|---|---|---|---|---|---|
 | |||||||
| Identifiers | |||||||
| Organism | Ricinus communis | ||||||
| Symbol | RCOM_2159910 | ||||||
| Entrez | 8287993 | ||||||
| RefSeq (mRNA) | XM_002534603.1 | ||||||
| RefSeq (Prot) | XP_002534649.1 | ||||||
| UniProt | P02879 | ||||||
| Other data | |||||||
| EC number | 3.2.2.22 | ||||||
| Chromosome | whole genome: 0 - 0.01 Mb | ||||||
| |||||||
| Ribosome-inactivating protein (Ricin A chain) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | RIP | ||||||||
| Pfam | PF00161 | ||||||||
| InterPro | IPR001574 | ||||||||
| PROSITE | PDOC00248 | ||||||||
| SCOP2 | 1paf /SCOPe /SUPFAM | ||||||||
| |||||||||
| Ricin-type beta-trefoil lectin domain (Ricin B chain) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | N/A | ||||||||
| Pfam | PF00652 | ||||||||
| Pfam clan | CL0066 | ||||||||
| PROSITE | IPR000772 | ||||||||
| SCOP2 | 1abr /SCOPe /SUPFAM | ||||||||
| CAZy | CBM13 | ||||||||
| CDD | cd00161 | ||||||||
| |||||||||
Ricin (/ˈraɪsɪn/RY-sin) is alectin (a carbohydrate-bindingprotein) and a highly potenttoxin produced in the seeds of thecastor oil plant,Ricinus communis. Themedian lethal dose (LD50) of ricin for mice is around 22micrograms per kilogram of body mass viaintraperitoneal injection. Oral exposure to ricin is far less toxic. An estimated lethal oral dose in humans is approximately one milligram per kilogram of body mass.[1]
Ricin is atoxalbumin and was first described byPeter Hermann Stillmark, the founder oflectinology. Ricin is chemically similar torobin.
Ricin is classified as a type 2ribosome-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 aheterodimeric complex. Type 2 RIPs consist of an A chain that is functionally equivalent to a type 1 RIP, covalently connected by a singledisulfide 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 theendoplasmic reticulum (ER). Both type 1 and type 2 RIPs are functionally active against ribosomesin vitro; however, only type 2 RIPs displaycytotoxicity due to thelectin-like properties of the B chain. To display its ribosome-inactivating function, the ricin disulfide bond must bereductively cleaved.[2]
Ricin issynthesized in theendosperm of castor oil plant seeds.[3] The ricinprecursor protein is 576amino acid residues in length and contains asignal peptide (residues 1–35), the ricin A chain (36–302), a linker peptide (303–314), and the ricin B chain (315–576).[4] TheN-terminal signal sequence delivers the prepropolypeptide to theendoplasmic reticulum (ER) and then the signal peptide is cleaved off. Within thelumen of the ER the propolypeptide isglycosylated and aprotein disulfide isomerase catalyzesdisulfide bond formation betweencysteines 294 and 318. The propolypeptide is further glycosylated within theGolgi apparatus and transported to protein storage bodies. The propolypeptide is cleaved within protein bodies by anendopeptidase 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.[3]
In terms of structure, ricin closely resembles abrin-a, an isomer ofabrin. Thequaternary structure of ricin is a globular, glycosylated heterodimer of approximately 60–65kDa.[5] Ricin toxin A chain and ricin toxin B chain are of similar molecular weights, approximately 32 kDa and 34 kDa, respectively.
While other plants contain the protein chains found in ricin, both protein chains must be present to produce toxic effects. For example, plants that contain only protein chain A, such asbarley, are not toxic because without the link to protein chain B, protein chain A cannot enter the cell and do damage to ribosomes.[8]
Ricin B chain binds complex carbohydrates on the surface ofeukaryotic cells containing either terminalN-acetylgalactosamine or beta-1,4-linked galactose residues. In addition, themannose-typeglycans of ricin are able to bind to cells that expressmannose receptors.[9] RTB has been shown to bind to the cell surface on the order of 106–108 ricin molecules per cell surface.[10]
The profuse binding of ricin to surface membranes allows internalization with all types of membraneinvaginations. The holotoxin can be taken up byclathrin-coated pits, as well as by clathrin-independent pathways includingcaveolae andmacropinocytosis.[11][12] Intracellularvesicles shuttle ricin toendosomes that are delivered to theGolgi 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 orlysosomes offers little or no protection against ricin.[13] Ricin molecules are thought to followretrograde transport via early endosomes, the trans-Golgi network, and the Golgi to enter thelumen of theendoplasmic reticulum (ER).[14]
For ricin to function cytotoxically, RTA must be reductively cleaved from RTB to release asteric 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.[15][16] 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.[17] Roles for the ER chaperonesGRP94,[18]EDEM[19] andBiP[20] have been proposed prior to the 'dislocation' of RTA from the ER lumen to the cytosol in a manner that uses 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 E3ubiquitin ligase complexes,[21] but RTA avoids theubiquitination that usually occurs with ERAD substrates because of its low content oflysine residues, which are the usual attachment sites forubiquitin.[22] 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 chaperonesHsc70 andHsp90 and their co-chaperones, as well as by one subunit (RPT5) of theproteasome itself, that results in its folding to a catalytic conformation,[18][23] which de-purinatesribosomes, thus halting protein synthesis.
RTA hasrRNAN-glycosylase activity that is responsible for the cleavage of aglycosidic bond within the largerRNA of the60S subunit of eukaryotic ribosomes.[24] RTA specifically and irreversiblyhydrolyses theN-glycosidic bond of theadenine residue at position 4324 (A4324) within the28S rRNA, but leaves thephosphodiester backbone of the RNA intact.[25] The ricin targets A4324 that is contained in a highlyconserved sequence of 12nucleotides universally found in eukaryotic ribosomes. The sequence, 5'-AGUACGAGAGGA-3', termed the sarcin-ricin loop, is important in bindingelongation factors during protein synthesis.[26] The depurination event rapidly and completely inactivates the ribosome, resulting in toxicity from inhibited protein synthesis. A single RTA molecule in thecytosol is capable of depurinating approximately 1500ribosomes per minute.
Within the active site of RTA, there exist several invariant amino acid residues involved in thedepurination of ribosomal RNA.[13] Although the exact mechanism of the event is unknown, key amino acid residues identified includetyrosine at positions 80 and 123,glutamic acid at position 177, andarginine at position 180. In particular, Arg180 and Glu177 have been shown to be involved in thecatalytic mechanism, and not substrate binding, withenzyme kinetic studies involving RTA mutants. The model proposed by Mozingo and Robertus,[6] based on X-ray structures, is as follows:
Ricin is very toxic ifinhaled,injected, oringested. It can also be toxic if dust contacts the eyes or if it is absorbed through damaged skin. It acts as a toxin by inhibitingprotein synthesis.[27][28] Ricin is resistant, but not impervious, to digestion bypeptidases. 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 good recovery.[29][30]
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 six hours; these symptoms do not always become apparent. Within two to five days of exposure to ricin, its effects on thecentral nervous system,adrenal glands,kidneys, andliver appear.[28]
Ingestion of ricin causes pain, inflammation, and hemorrhage in the mucosal membranes of the gastrointestinal system. Gastrointestinal symptoms quickly progress to severe nausea, vomiting,diarrhea, and difficulty swallowing (dysphagia). Haemorrhage causes bloody feces (melena) and vomiting blood (hematemesis). The low blood volume (hypovolemia) caused by gastrointestinal fluid loss can lead to organ failure in thepancreas, kidney, liver, and GI tract and progress to shock. Shock and organ failure are indicated bydisorientation, stupor, weakness, drowsiness, excessive thirst (polydipsia), low urine production (oliguria), and bloody urine (hematuria). Victims can die ofcirculatory shock or organ failure; death typically occur between 3 and 5 days after oral ingestion.[28]
Symptoms of ricin inhalation are different from those caused by ingestion. Early symptoms include a cough and fever.[28] It can cause fatalpulmonary edema orrespiratory failure.[28]
When skin or inhalation exposure occur, ricin can cause anallergic reaction to develop. This is indicated by swelling (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.[28]
Anantidote has been developed by the UK military, although as of 2006 it has not yet been tested on humans.[31][32] As of 2005 another antidote developed by the US military has been shown to be safe and effective in lab mice injected withantibody-rich blood mixed with ricin, and has had some human testing.[33]Monoclonal antibodies are under scientific investigation as a possible treatment for ricin poisoning.[34]
Symptomatic and supportive treatments are available for ricin poisoning. Existing treatments emphasize minimizing the effects of the poison. Possible treatments includeintravenous fluids or electrolytes,airway management,assisted ventilation, or giving medications to remedy seizures and low blood pressure. If the ricin has been ingested recently, the stomach can be flushed by ingestingactivated charcoal or by performinggastric lavage. Survivors often develop long-term organ damage.[28]
Vaccination is possible by injecting an inactive form of protein chain A.[8] 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 onGeorgi 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.[8]
The seeds ofRicinus communis are commonly crushed to extractcastor oil. As ricin is not oil-soluble, little is found in the extracted castor oil.[8] The extracted oil is also heated to more than 80 °C (176 °F) todenature any ricin that may be present.[8] The remaining spent crushed seeds, called variously the "cake", "oil cake", and "press cake", can contain up to 5% ricin.[35] While the oil cake from coconut, peanuts, and sometimes cotton seeds can be used as cattle feed or fertilizer, the toxic nature of castor beans precludes their oil cake from being used as feed unless the ricin is first deactivated byautoclaving.[36] Accidental ingestion ofRicinus communis cake intended for fertilizer has been reported to be responsible for fatal ricin poisoning in animals.[27][37]
Deaths from ingesting castor plant seeds are rare, partly because of their indigestibleseed coat, and because some of the ricin is deactivated in the stomach.[38] The pulp from eight beans is considered dangerous to an adult.[39] Rauber and Heard have written that close examination of early 20th centurycase reports indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management".[40]
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. Swallowing castor beans rarely proves to be fatal unless the bean is thoroughly chewed. The survival rate of castor bean ingestion is 98%.[8] In 2013 a 37-year-old woman in the United States survived after ingesting 30 beans.[41] In another case, a man ingested 200 castor beans mixed with juice in a blender and survived.[42] Victims often manifestnausea,diarrhea,fast heart rate,low blood pressure, andseizures persisting for up to a week.[27] Blood, plasma, or urine ricin orricinine concentrations may be measured to confirm diagnosis. The laboratory testing usually involves immunoassay orliquid chromatography-mass spectrometry.[43]
 | This sectionneeds additional citations forverification. Please helpimprove this article byadding citations to reliable sources in this section. Unsourced material may be challenged and removed.(March 2014) (Learn how and when to remove this message) |
Although no approved therapeutics are based on ricin, it does have the potential to be used in thetreatment of tumors, as a "magic bullet" to destroy targeted cells.[13] Because ricin is a protein, it can be linked to amonoclonal antibody[44] to targetcancerous cells recognized by the antibody. The major problem with ricin is that its nativeinternalization 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 theseimmunotoxins 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 asdiphtheria toxin, which is used indenileukin 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 deliveringantigens into cells, thus greatly increasing theirimmunogenicity. Use of ricin as anadjuvant has potential implications for developingmucosalvaccines.
In the US, ricin appears on theselect agents list of theDepartment of Health and Human Services,[45] and scientists must register with HHS to use ricin in their research. However, investigators under the control of less than 1000 mg are exempt from regulation.[46]
Ricin is classified as anextremely hazardous substance in the United States as defined in Section 302 of the USEmergency 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.[47]
The United States investigated ricin for its military potential duringWorld War I.[48] At that time it was being considered for use either as a toxic dust or as a coating for bullets andshrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate theHague Convention of 1899 (adopted in U.S. law at 32Stat. 1903), specifically Annex §2, Ch.1, Article 23, stating "... it is especially prohibited ... [t]o employ poison or poisoned arms".[49]
In 'Ricin and Abrin', Manashi Bagchi, Shirley Zafra-Stone, Francis C. Lau, and Debasis Bagchi wrote that duringWorld War II the United States and Canada studied ricin incluster bombs.[50] Though there were plans for mass production and several field trials with different bomblet concepts, the end conclusion was that it was no more economical than usingphosgene. This conclusion was based on comparison of the final weapons, rather than ricin's toxicity (LCt50 ~10 mg/min·m3).[citation needed] Ricin was given themilitary symbolW or laterWA.[citation needed] Interest in it continued for a short period after World War II, but soon subsided when theUS Army Chemical Corps began a program to weaponizesarin.[51]
TheSoviet Union possessed weaponized ricin. TheKGB developed weapons using ricin which were used outside theSoviet bloc, most famously in theMarkov assassination.[52][53]
In spite of ricin's extremetoxicity and utility as an agent of chemical/biological warfare, production of the toxin is difficult to limit. Thecastor bean plant from which ricin is derived is a commonornamental and can be grown at home without any special care.
Under both the 1972Biological Weapons Convention and the 1997Chemical Weapons Convention, ricin is listed as aschedule 1 controlled substance. Despite this, more than 1 million metric tons (1,100,000 short tons) 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.[54]
Ricin is several orders of magnitude less toxic thanbotulinum ortetanus toxin, but the latter are harder to come by. Compared to botulinum oranthrax asbiological weapons orchemical weapons, the quantity of ricin required to achieve LD50 over a large geographic area (100 km2) is significantly more than an agent such as anthrax (8 tonnes of ricin vs. only kilogram quantities of anthrax).[55] Ricin is easy to produce, but is not as practical or likely to cause as many casualties as other agents.[29] Ricin is easily denatured by temperatures over 80 °C (176 °F) meaning many methods of deploying ricin would generate enough heat to denature it.[35] 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.[8] In contrast, anthraxspores may remain lethal for decades.Jan van Aken, a German expert on biological weapons, explained in a report forThe Sunshine Project thatAl Qaeda's experiments with ricin suggest their inability to producebotulinum or anthrax.[56]
Ricin toxin vaccines have emerged as a focus inbiodefense research. Two recombinant A subunit (RTA)-based vaccines, RiVax and RVEc (also known as RTA1-33/44-198),[59][60] have completed Phase I clinical trials, and were found to be safe.[61] These vaccines are based on modified versions of the ricin toxin A-chain, designed to reduce toxicity while maintainingimmunogenicity.
A biopharmaceutical company called Soligenix, Inc. licensed an anti-ricin vaccine called RiVax[62] from Vitetta et al. atUT Southwestern. The vaccine was found safe and immunogenic in mice, rabbits, and humans. Two successful clinical trials were completed.[63] Soligenix was issued a US patent for Rivax. The ricin vaccine candidate was granted orphan drug status in the US and the EEC and, as of 2019, was in clinical trials in the US. Grants from the National Institute of Allergy and Infectious Diseases and the US Food and Drug Administration supported development of the vaccine candidate.[64]
The first isolation of ricin is attributed to the Baltic-German microbiologistPeter Hermann Stillmark (1860–1923) in 1888.[65][66][67]
Ricin has been involved in a number of actual or planned attacks on individuals. As of 2025[update], the only successful murder using ricin occurred in 1978.[68] The Bulgarian dissidentGeorgi Markov was assassinated byBulgarian secret police who surreptitiously shot him on a London street with what was later found to have been amodified umbrella usingcompressed gas to fire a tiny pellet containing ricin into his leg.[29][69] He died in a hospital a few days later; his body was passed to a special poison branch of theBritish Ministry of Defence that discovered the pellet during anautopsy. The prime suspects were the Bulgarian secret police: Georgi Markov haddefected from Bulgaria some years previously and had subsequently written books and made radio broadcasts that were highly critical of the Bulgariancommunist 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 defectorsOleg Kalugin andOleg Gordievsky later confirmed the KGB's involvement. Soviet dissidentAleksandr Solzhenitsyn developed (but survived) ricin-like symptoms after an encounter in 1971 with KGB agents.[70]
Ten days before the attack on Georgi Markov another Bulgarian defector,Vladimir Kostov, survived a similar attack. 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.[8]
Several terrorist individuals and groups have experimented with ricin or planned to use it.[71] There have been incidents of the poison being mailed to US politicians. For example, on 29 May 2013 two anonymous letters sent to New York City MayorMichael Bloomberg contained traces of it.[72] Another was sent to the offices ofMayors Against Illegal Guns in Washington, D.C. A letter containing ricin was also reported to have been sent to American PresidentBarack Obama at the same time.Shannon Richardson, an actress, was later charged with the crime, and pleaded guilty that December;[73] she was sentenced to 18 years in prison plus arestitution fine ofUS$367,000.[74] On 2 October 2018, two letters suspected of containing ricin were sent toThe Pentagon, one addressed to Secretary of DefenseJames Mattis, and the other to Chief of Naval Operations, AdmiralJohn Richardson.[75] A letter was received on 23 July 2019 atPelican Bay State Prison in California which claimed to contain a suspicious substance. Authorities later confirmed it contained ricin; no detrimental exposures were identified.[76]
In 2020, some media in the Czech Republic reported, based on intelligence information, that a person carrying a Russian diplomatic passport and ricin had arrived in Prague with the intention of assassinating three politicians. Russian presidentVladimir Putin denied the reports. The targets were said to have beenZdeněk Hřib, the mayor ofPrague (capital of the Czech Republic), who was involved in renaming a square in Prague, "Pod Kaštany", where the Russian embassy is situated, to the Square ofBoris Nemtsov, an opposition politician assassinated in theKremlin in 2015;Ondřej Kolář, the mayor ofPrague 6 municipal district, who was involved in removing the controversial statue to the Soviet-eraMarshal Konev; andPavel Novotný, the mayor of Prague's southwesternŘeporyje district. They all received police protection.[77][78] Czech presidentMiloš Zeman later described the police protection of Zdeněk Hřib as an attempt by an insignificant politician to gain attention. Zeman also confused ricin with non-poisonouslaxativecastor oil.[79]
In 2018[80] and 2023 German police thwarted attempted ricin attacks, after tip-offs believed to have come from the USFBI.[81]
Ricin has been used as a plot device, such as in the television seriesBreaking Bad.[82]
The popularity ofBreaking Bad inspired several real-life criminal cases involving ricin or similar substances. Kuntal Patel from London attempted to poison her mother withabrin after the latter interfered with her marriage plans.[83] Daniel Milzman, a 19-year-old formerGeorgetown 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".[84] Mohammed Ali fromLiverpool, England, was convicted after attempting to purchase 500 mg of ricin over thedark web from an undercoverFBI agent. He was sentenced on 18 September 2015 to eight years imprisonment.[85]
InAgatha Christie's 1929 short storyThe House of Lurking Death, ricin is used as a plot device.[86]
| International | |
|---|---|
| National | |
| Other | |
